Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 135
Healthy volunteers: no

Brief summary:
This is a Phase IIa, randomized, placebo-controlled, double-blind, multicenter, two-arm study to evaluate the efficacy, safety, and pharmacokinetics of MTPS9579A as an add-on therapy in patients with uncontrolled moderate to severe asthma who are receiving daily ICS therapy and at least one of the following additional controller medications: long-acting beta-agonist (LABA), leukotriene modulator (leukotriene modifier \[LTM\] or leukotriene receptor antagonist \[LTRA\]), long-acting muscarinic antagonist (LAMA), or long-acting theophylline preparation.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: MTPS9579A intervention 2: Placebo
Intervention descriptions: intervention 1: MTPS9579A IV infusion will be administered at the randomization visit (Week 2), Week 6, and every 4 weeks through Week 46. intervention 2: Placebo matching MTPS9579A will be administered at the randomization visit (Week 2), Week 6, and every 4 weeks thereafter through Week 46.

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable 
Ethics Committee or Institutional Review Board.  It is understood that this information will not be 
disclosed to others without written authorization from Genentech except to the extent necessary to 
obtain informed consent from persons to whom the drug may be administered.
MTPS9579A—Genentech, Inc.
Protocol GB41149, Version 4
PROTOCOL
TITLE:
A PHASE IIa, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND 
STUDY TO EVALUATE THE EFFICACY, SAFETY, 
AND PHARMACOKINETICS OF MTPS9579A IN 
PATIENTS WITH ASTHMA REQUIRING INHALED 
CORTICOSTEROIDS AND A SECOND 
CONTROLLER
PROTOCOL NUMBER:
GB41149
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-000795-41
IND NUMBER:
NCT NUMBER:
NCT04092582
TEST PRODUCT:
MTPS9579A (RO7198434)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
APPROVAL DATE:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
18-Sep-2021 03:41:26


MTPS9579A—Genentech, Inc.
2/Protocol GB41149, Version 4
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
4
See electronic date 
stamp on title page
Germany
4
See electronic date 
stamp on title page
3
22 November 2019
Germany
3
1 April 2020
2
22 August 2019
Poland
2
22 November 2019
1
20 June 2019







MTPS9579A—Genentech, Inc.
4/Protocol GB41149, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 25
1.1
Background on Asthma ......................................................... 25
1.2
Background on MTPS9579A ................................................. 26
1.3
Study Rationale and Benefit-Risk Assessment...................... 26
2.
OBJECTIVES AND ENDPOINTS ............................................................... 26
2.1
Efficacy Objectives ................................................................ 27
2.1.1
Primary Efficacy Objective..................................................... 27
2.1.2
Secondary Efficacy Objective................................................ 27
2.1.3
Exploratory Efficacy Objective............................................... 28
2.2
Safety Objective .................................................................... 28
2.3
Pharmacokinetic Objectives .................................................. 28
2.4
Immunogenicity Objectives.................................................... 29
2.5
Biomarker Objective .............................................................. 29
3.
STUDY DESIGN......................................................................................... 30
3.1
Overview of the Study Design ............................................... 30
3.1.1
Screening Period................................................................... 33
3.1.2
Run-In Period ........................................................................ 33
3.1.3
Internal Monitoring Committee............................................... 33
3.2
End of Study and Length of Study......................................... 34
3.3
Rationale for Study Design.................................................... 34
3.3.1
Rationale for MTPS9579A Dose and Schedule..................... 34
3.3.2
Rationale for Patient Population ............................................ 35
3.3.3
Rationale for Control Group................................................... 35
3.3.4
Rationale for Biomarker Assessments................................... 36
3.3.5
Rationale for Optional Methacholine Challenge 
Test........................................................................................ 36
4.
MATERIALS AND METHODS .................................................................... 36


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5/Protocol GB41149, Version 4
4.1
Patients.................................................................................. 36
4.1.1
Inclusion Criteria.................................................................... 36
4.1.1.1
Inclusion Criteria for Enrollment in the Run-In 
Period .................................................................................... 36
4.1.1.2
Inclusion Criteria for Enrollment in the Double-
Blind Treatment Period.......................................................... 38
4.1.1.3
Inclusion Criteria for the Optional Methacholine 
Challenge Test ...................................................................... 39
4.1.2
Exclusion Criteria................................................................... 39
4.2
Method of Treatment Assignment and Blinding..................... 42
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 43
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 43
4.3.1.1
MTPS9579A and Placebo ..................................................... 43
4.3.1.2
Other Protocol-Mandated Asthma Medications ..................... 44
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 44
4.3.3
Investigational Medicinal Product Accountability ................... 44
4.3.4
Continued Access to MTPS9579A ........................................ 45
4.4
Concomitant Therapy and Additional Restrictions................. 45
4.4.1
Permitted Asthma Therapy.................................................... 45
4.4.1.1
Short-Acting Rescue Therapy................................................ 46
4.4.1.2
Systemic Corticosteroid Use.................................................. 46
4.4.2
Cautionary Therapy ............................................................... 46
4.4.3
Asthma Therapy and Concomitant Restrictions..................... 46
4.4.4
Prohibited Medication Use Prior to Peak 
Expiratory Flow Rate and Spirometry 
Measurements....................................................................... 48
4.5
Study Assessments ............................................................... 49
4.5.1
Informed Consent Forms and Screening Log........................ 49
4.5.2
Medical History, Concomitant Medications, and 
Demographic Data................................................................. 49
4.5.3
Physical Examinations........................................................... 49
4.5.4
Vital Signs.............................................................................. 50
4.5.5
Nasosorption ......................................................................... 50


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6/Protocol GB41149, Version 4
4.5.6
Fractional Exhaled Nitric Oxide ............................................. 50
4.5.7
Spirometry ............................................................................. 50
4.5.8
Assessments Completed by the Patient at Home.................. 51
4.5.8.1
Daily Diary Symptom-Related Asthma 
Assessments ......................................................................... 52
4.5.8.2
Peak Expiratory Flow Rate .................................................... 52
4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 52
4.5.10
Electrocardiograms................................................................ 54
4.5.11
Chest X-Rays ........................................................................ 55
4.5.12
Asthma Exacerbations........................................................... 55
4.5.13
Blood Samples for Whole Genome Sequencing 
(Patients at Participating Sites).............................................. 55
4.5.14
Optional Methacholine Challenge Test.................................. 56
4.5.15
Optional Samples for Research Biosample 
Repository ............................................................................. 56
4.5.15.1
Overview of the Research Biosample Repository.................. 56
4.5.15.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 57
4.5.15.3
Sample Collection.................................................................. 57
4.5.15.4
Confidentiality........................................................................ 58
4.5.15.5
Consent to Participate in the Research 
Biosample Repository............................................................ 58
4.5.15.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 59
4.5.15.7
Monitoring and Oversight....................................................... 59
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 59
4.6.1
Study Treatment Discontinuation........................................... 59
4.6.2
Patient Discontinuation from the Study.................................. 60
4.6.3
Study Discontinuation............................................................ 60
4.6.4
Site Discontinuation............................................................... 61
5.
ASSESSMENT OF SAFETY....................................................................... 61
5.1
Safety Plan ............................................................................ 61
5.1.1
Risks Associated with MTPS9579A....................................... 61


MTPS9579A—Genentech, Inc.
7/Protocol GB41149, Version 4
5.1.1.1
Immunogenicity ..................................................................... 62
5.1.1.2
Hypersensitivity/Hypersensitivity-Like Reactions 
and Anaphylaxis/Anaphylactoid Reactions............................ 62
5.1.1.3
Infusion-Related Reactions.................................................... 63
5.1.1.4
Injection-Site Reactions......................................................... 63
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 64
5.1.2.1
Treatment Interruption ........................................................... 64
5.1.2.2
Management Guidelines for Hepatotoxicity ........................... 64
5.1.2.3
Management of Increases in QT Interval............................... 65
5.2
Safety Parameters and Definitions ........................................ 66
5.2.1
Adverse Events ..................................................................... 66
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 67
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 67
5.2.4
Selected Adverse Events....................................................... 68
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 68
5.3.1
Adverse Event Reporting Period ........................................... 68
5.3.2
Eliciting Adverse Event Information....................................... 69
5.3.3
Assessment of Severity of Adverse Events ........................... 69
5.3.4
Assessment of Causality of Adverse Events ......................... 69
5.3.5
Procedures for Recording Adverse Events............................ 70
5.3.5.1
Infusion-Related or Injection Reactions ................................. 70
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 70
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 71
5.3.5.4
Persistent or Recurrent Adverse Events................................ 71
5.3.5.5
Abnormal Laboratory Values ................................................. 72
5.3.5.6
Abnormal Vital Sign Values ................................................... 72
5.3.5.7
Abnormal Liver Function Tests.............................................. 73
5.3.5.8
Deaths ................................................................................... 73
5.3.5.9
Preexisting Medical Conditions.............................................. 74
5.3.5.10
Worsening of Asthma ............................................................ 74


MTPS9579A—Genentech, Inc.
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5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 74
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 75
5.3.5.13
Patient-Reported Outcome Data ........................................... 76
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 76
5.4.1
Emergency Medical Contacts................................................ 77
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 77
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 77
5.4.2.2
Events That Occur after Study Drug Initiation........................ 77
5.4.3
Reporting Requirements for Pregnancies.............................. 78
5.4.3.1
Pregnancies in Female Patients............................................ 78
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 78
5.4.3.3
Abortions ............................................................................... 79
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 79
5.5
Follow-Up of Patients after Adverse Events .......................... 79
5.5.1
Investigator Follow-Up........................................................... 79
5.5.2
Sponsor Follow-Up ................................................................ 79
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 80
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 80
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 80
6.1
Determination of Sample Size ............................................... 81
6.2
Summaries of Conduct of Study............................................ 81
6.3
Summaries of Treatment Group Comparability ..................... 82
6.4
Efficacy Analyses .................................................................. 82
6.4.1
Primary Efficacy Endpoint...................................................... 82
6.4.2
Secondary Efficacy Endpoints............................................... 83
6.4.3
Exploratory Efficacy Endpoints.............................................. 84
6.5
Safety Analyses..................................................................... 85
6.6
Pharmacokinetic Analyses..................................................... 85


MTPS9579A—Genentech, Inc.
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6.7
Immunogenicity Analyses...................................................... 85
6.8
Biomarker Analyses............................................................... 86
6.9
Interim Analyses .................................................................... 86
6.9.1
Planned Interim Analysis ....................................................... 86
6.9.2
Optional Interim Analyses...................................................... 87
7.
DATA COLLECTION AND MANAGEMENT ............................................... 87
7.1
Data Quality Assurance......................................................... 87
7.2
Electronic Case Report Forms............................................... 87
7.3
Electronic Patient-Reported Outcome Data........................... 88
7.4
Source Data Documentation.................................................. 88
7.5
Use of Computerized Systems .............................................. 89
7.6
Retention of Records............................................................. 89
8.
ETHICAL CONSIDERATIONS.................................................................... 89
8.1
Compliance with Laws and Regulations ................................ 89
8.2
Informed Consent.................................................................. 90
8.3
Institutional Review Board or Ethics Committee.................... 91
8.4
Confidentiality........................................................................ 91
8.5
Financial Disclosure .............................................................. 92
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 92
9.1
Study Documentation ............................................................ 92
9.2
Protocol Deviations................................................................ 92
9.3
Management of Study Quality ............................................... 93
9.4
Site Inspections ..................................................................... 93
9.5
Administrative Structure......................................................... 93
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 93
9.7
Protocol Amendments ........................................................... 94
10. REFERENCES ........................................................................................... 95


MTPS9579A—Genentech, Inc.
10/Protocol GB41149, Version 4
LIST OF TABLES
Table 1
Asthma Therapy and Concomitant Therapy Restrictions............ 47
Table 2
Guidelines for Treatment Interruption or Discontinuation for 
Patients Who Experience Hepatotoxicity .................................... 65
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 69
Table 4
Causal Attribution Guidance ....................................................... 70
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 32
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 98
Appendix 2
Asthma Control Questionnaire, 5-Item Version......................... 104
Appendix 3
Tuberculosis Worksheet............................................................ 107
Appendix 4 
Daytime eDiary ......................................................................... 109
Appendix 5 
Nighttime eDiary ....................................................................... 110
Appendix 6
Anaphylaxis Precautions and Diagnosis................................... 111
Appendix 7
WHO Toxicity Grading Scale .................................................... 113
Appendix 8
Detailed Definition of Diary Worsening Events.......................... 117


MTPS9579A—Genentech, Inc.
11/Protocol GB41149, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IIa, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY 
TO EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF MTPS9579A IN 
PATIENTS WITH ASTHMA REQUIRING INHALED 
CORTICOSTEROIDS AND A SECOND 
CONTROLLER
PROTOCOL NUMBER:
GB41149
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-000795-41
IND NUMBER:
TEST PRODUCT:
MTPS9579A (RO7198434)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of the 
signed form to the Sponsor Representative.


MTPS9579A—Genentech, Inc.
12/Protocol GB41149, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE IIa, MULTICENTER, RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE-BLIND STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF MTPS9579A 
IN PATIENTS WITH ASTHMA REQUIRING INHALED 
CORTICOSTEROIDS AND A SECOND CONTROLLER
PROTOCOL NUMBER:
GB41149
VERSION NUMBER:
4
EUDRACT NUMBER:
2019-000795-41
IND NUMBER:
TEST PRODUCT:
MTPS9579A (RO7198434)
PHASE:
IIa
INDICATION:
Asthma
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of MTPS9579A compared 
with placebo in patients with uncontrolled asthma despite the use of inhaled corticosteroids 
(ICS) and a second controller.  Specific objectives and corresponding endpoints for the study 
are outlined below.
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of MTPS9579A compared 
with placebo on the basis of the following endpoint:

Time to first CompEx event, a composite endpoint defined as time from randomization to 
first asthma exacerbation or diary worsening during the 48-week double-blind treatment 
period (from the randomization visit [Week 2] to end of treatment [Week 50]).  Asthma 
exacerbations and diary worsening are defined as follows: 
Asthma exacerbations are assessed by the investigator and defined as new or increased 
asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/ or nighttime 
awakenings due to these symptoms) that result in one or both of the following:
Hospitalization or an emergency department or urgent care visit requiring 
administration of systemic corticosteroid treatment
Treatment with systemic (IV, intramuscular [IM], or oral) corticosteroids for 3 days or 
a long-acting depot corticosteroid preparation with a therapeutic effectiveness of 
3 days
Diary worsening is based on the occurrence of prespecified changes (deteriorations) in a 
subset of the following six parameters:  morning peak expiratory flow rate (PEFR), evening 
PEFR, morning symptom score, evening symptom score, morning short-acting rescue 
therapy use, and evening short-acting rescue therapy use.  A detailed definition of diary 
worsening is provided in the protocol.


MTPS9579A—Genentech, Inc.
13/Protocol GB41149, Version 4
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of MTPS9579A 
compared with placebo on the basis of the following endpoints:

Rate of asthma exacerbations (as defined in primary efficacy objective and assessed by the 
investigator) during the 48-week double-blind treatment period

Time to first asthma exacerbation during the 48-week double-blind treatment period

Absolute and relative change from randomization in pre-bronchodilator forced expiratory 
volume in 1 second (FEV1; liters) at Week 50

Absolute and relative change from randomization in fractional exhaled nitric oxide (FeNO) 
at Week 50
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of MTPS9579A 
compared with placebo on the basis of the following endpoints:

Rate of severe asthma exacerbations during the 48-week double-blind treatment period, 
defined as asthma symptoms requiring hospitalization or resulting in death attributed to 
asthma

Absolute change from randomization in pre-bronchodilator FEV1 (percentage predicted) at 
Week 50

Absolute change from randomization in patient-reported daytime asthma symptom severity, 
as measured by a daily symptom diary (as defined in primary efficacy objective), at 
Week 50

Absolute change from randomization in patient-reported nighttime asthma symptom 
severity, as measured by a daily symptom diary (as defined in primary efficacy objective), at 
Week 50

Absolute change from randomization in patient-reported number of puffs of short-acting 
rescue inhaler or number of times nebulizer was used at Week 50

Absolute and relative change from randomization visit in provocative dose of methacholine 
causing a 20% drop in FEV1 (PD20) as a measure of airway hyper-responsiveness at Week 
30, in patients who consent to this optional assessment at select sites
Safety Objective
The safety objective for this study is to evaluate the safety of MTPS9579A compared with 
placebo on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to the WHO 
Toxicity Grading Scale

Change from randomization visit in physical examination findings 

Change from randomization visit in vital signs 

Change from randomization visit in ECG parameters 

Change from randomization visit in clinical laboratory results
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize the MTPS9579A PK profile 
on the basis of the following endpoint:

Serum concentration of MTPS9579A at specified timepoints
The exploratory PK objective for this study is to characterize concentrations of MTPS9579A in 
nasal mucosal lining fluid and to evaluate potential relationships between drug exposure and 
the efficacy and safety of MTPS9579A on the basis of the following endpoints:

Relationship between serum concentration, nasal mucosal lining fluid concentration, or PK 
parameters for MTPS9579A and efficacy or pharmacodynamic (PD) endpoints

Relationship between serum concentration, nasal mucosal lining fluid concentration, or PK 
parameters for MTPS9579A and safety endpoints


MTPS9579A—Genentech, Inc.
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Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to MTPS9579A 
on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) during the study relative to the prevalence of 
ADAs at the randomization visit
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK/PD endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to MTPS9579A (i.e., predictive biomarkers), can provide evidence of 
MTPS9579A activity (i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoints:

Change from the randomization visit in biomarker levels in nasal mucosal lining fluid, urine, 
and serum samples

Relationship among biomarker levels in nasal mucosal lining fluid, urine, and serum 
samples

Relationship between biomarkers in nasal mucosal lining fluid, urine, and serum and 
efficacy, safety, PK, and immunogenicity endpoints

Rate of asthma exacerbations within subgroups defined by blood eosinophils during the 
48-week double-blind treatment period

Time to first CompEx event (as defined in primary efficacy objective) within subgroups 
defined by blood eosinophils during the 48-week double-blind treatment period

Rate of asthma exacerbations in subgroups defined by mutations in the genes encoding 
tryptase (TPSAB1 and TPSB2) during the 48-week double-blind treatment period

Time to first CompEx event (as defined in primary efficacy objective) in subgroups defined 
by mutations in the genes encoding tryptase (TPSAB1 and TPSB2) during the 48-week 
double-blind treatment period
Study Design
Description of Study
This is a Phase IIa, randomized, placebo-controlled, double-blind, multicenter, two-arm study of 
MTPS9579A compared with placebo as an add-on therapy in patients with uncontrolled 
moderate to severe asthma who are receiving daily ICS therapy and at least one of the 
following additional controller medications:  long-acting -agonist (LABA), leukotriene modulator 
(leukotriene modifier [LTM] or leukotriene receptor antagonist [LTRA]), long-acting muscarinic 
antagonist (LAMA), or long-acting theophylline preparation.  The study initially was to
randomize approximately 160 patients at approximately 55 sites globally.  However, as of 
March 2021, study enrollment was halted with 134 patients enrolled, and in August 2021, a 
decision was made to permanently halt further enrollment.
This study will consist of a 1228 day screening period, a 2-week single-blind placebo run-in 
period, a 48-week double-blind treatment period, a safety follow-up visit at Week 54, and a 
safety follow-up phone call at Week 58.  During the screening period, patients must 
demonstrate acceptable inhaler, peak flow meter, and spirometry techniques, in addition to 
compliance with required, twice-daily use of an electronic diary (eDiary) for answering questions 
related to asthma symptoms, PEFR, and short-acting rescue therapy use.  Patients who fail to 
meet eligibility criteria during the screening period will be permitted to re-screen once as 
described in the protocol.  
Patients who meet enrollment criteria for the run-in period will receive one single-blind dose of 
placebo (Week 0) to allow for the evaluation of variability in asthma control.  At the 
randomization visit (Week 2), patients must meet additional eligibility criteria for the double-blind 
treatment period that includes continued compliance with required, twice-daily use of the eDiary.  


MTPS9579A—Genentech, Inc.
15/Protocol GB41149, Version 4
Patients will be randomized in a 1:1 ratio to receive MTPS9579A (1800 mg IV every 4 weeks) or 
placebo.  Study drug will be administered by IV infusion at the randomization visit (Week 2),
Week 6, and every 4 weeks thereafter through Week 46.
During the treatment period, twice-daily assessment of asthma-related symptoms, PEFR, and 
use of short-acting rescue therapy will continue to be performed at home and recorded in the 
eDiary.  More detailed assessments, including spirometry and FeNO measurements, will be 
performed during scheduled site visits.  All patients will undergo PK, biomarker, and ADA 
sampling.  An additional exploratory efficacy assessment, the methacholine challenge test to 
assess airway reactivity, will be conducted at select sites in a subset of patients (approximately 
20 patients/study arm) who consent to this option and meet additional eligibility criteria. 
A planned interim analysis will take place once approximately 51 patients have experienced a 
CompEx event in the 48-week, double-blind treatment period.  The expected timing of this 
planned interim analysis is approximately 60 weeks after the first patient is randomized.  An 
optional interim analysis may also be conducted.  These interim analyses will be conducted for 
potential enrollment decisions (e.g., temporary or permanent enrollment halt, change to 
number of total randomized patients), for early study termination, or for administrative 
purposes (e.g., planning of future studies).
Screening Period
The screening period of up to 4 weeks is intended to allow sufficient time for a patient to meet 
all eligibility requirements.  Patients must complete at least 12 days of the screening period to 
demonstrate eDiary compliance.  Patients who are unable to complete assessments or meet 
eligibility requirements during the screening period will be permitted to be re-screened once for 
a total of up to two times. Within a screening period, patients who do not meet the requirement 
of pre-bronchodilator FEV1 of 40%80% or post-bronchodilator reversibility of FEV1 (liters) of 
12% and 200 mL are allowed up to two additional attempts to meet these two eligibility 
criteria, but only if their pre-bronchodilator FEV1 was between 35% and 85%.  
Patients who rescreen 6 weeks after Informed Consent Form completion must only repeat the 
assessments that triggered screen failure.  Patients who rescreen 6 weeks after Informed 
Consent Form completion are required to repeat the consent process and all screening 
assessments except tuberculosis (TB) screening and hepatitis serologies.  However, TB 
screening and hepatitis serologies should be repeated if the re-screening takes place 
6 months after initial screening or if there is risk of exposure.
Run-In Period
Patients enrolled in the run-in period will receive one single-blind dose of placebo at the run-in 
visit (Week 0).  eDiary compliance must continue to be demonstrated on at least 5 of 7 days 
during each of the 2 consecutive weeks of the run-in period.  Patients who do not meet eligibility 
criteria for the double-blind treatment period will be discontinued from the study and are not 
eligible for rescreening.
Internal Monitoring Committee
Periodic safety reviews will be performed by the Sponsor’s Internal Monitoring Committee (IMC) 
as outlined in the IMC Charter.  This committee will be unblinded to treatment assignments and 
will include a clinical scientist, drug safety scientist, biostatistician, and statistical programmer 
from the Sponsor.  The IMC members will not have direct contact with investigational staff or 
site monitors.  The IMC may decide to unblind the study team to enable decision-making.  The 
IMC may invite representatives from other functional areas on an ad-hoc basis when additional 
expertise is required (e.g., clinical pharmacology, research) or invite additional Sponsor 
scientists to participate in data analyses and review. 
The IMC will meet at a frequency dictated by the IMC charter but no less frequently than once 
every 3 months.  Additionally, ad-hoc IMC meetings may be convened immediately or 
expeditiously at any time to address potential safety concerns if periodic review of blinded 
safety data indicates 3 or more patients with serious or Grade 3 or higher adverse events 
(excluding asthma exacerbations) that the investigator or Sponsor determines to be related to 
study treatment, within the same MedDRA high level term.  The IMC will assess the severity, 
relatedness, and reversibility of adverse events, the degree of imbalance between treatment 
arms, the similarity and frequency of events under a single higher level term, the plausibility of a 


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common mechanism, possible risk mitigation measures, and may recommend changes to study 
conduct (including termination of study) as appropriate.
At any time during the study, the Sponsor may choose to inactivate and suspend enrollment 
and further dosing or reduce the dose due to safety concerns as recommended by the IMC.  
Should an ad-hoc IMC meeting be convened, enrollment of patients may be temporarily halted if 
warranted by the frequency and severity of the blinded adverse events, until the IMC evaluates 
the unblinded data and decides whether resumption of dosing is safe to proceed, or until IMC-
recommended changes to the conduct of the study are implemented.
Number of Patients
Approximately 160 patients with moderate to severe asthma were originally planned to be 
randomized in this study (80 patients in each of 2 treatment arms); however, as of August 2021, 
study enrollment has been halted with 134 patients enrolled.
Target Population
Inclusion Criteria
Inclusion Criteria for Enrollment in the Run-In Period
Patients must meet the following criteria for enrollment in the run-in period:

Signed Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Age 1875 years, inclusive, at the time of signing the Informed Consent Form

Body mass index of 1838 kg/m2 and weight 40 kg at screening

Documented physician-diagnosed asthma for at least 12 months prior to screening 

Pre-bronchodilator FEV1 40%80% predicted at screening 

Post-bronchodilator reversibility of FEV1 (liters) 12% and 200 mL at screening
Post-bronchodilator reversibility testing, including medication-withholding strategies 
and appropriate dosing of short-acting bronchodilators, should be performed per 
American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines 
(Miller et al. 2005).
Alternative evidence demonstrating variable expiratory airway limitation may be 
considered after discussion with the Medical Monitor.

Treatment with asthma controller therapy (daily ICS [100 g of fluticasone propionate or 
equivalent] and at least one additional controller therapy [LABA, LAMA, LTM/LTRA]) for 
3 months prior to screening, with no changes within 4 weeks prior to screening or during 
the screening period and no anticipated changes in controller dosing regimens throughout 
the study
For patients receiving a total daily ICS dose of 500 g fluticasone propionate or 
equivalent, one of their additional controller therapies must be LABA.
For patients receiving a total daily ICS dose of 500 g fluticasone propionate or 
equivalent, they must receive one or more of the following additional controller 
therapies:  LABA, LTM/LTRA, LAMA, or long-acting theophylline preparations.

Asthma Control Questionnaire, 5-item version score 1.5 at screening

Documented history (e.g., medical report, pharmacy prescription assessed by investigator) 
of 2 asthma exacerbations within the 12 months prior to screening while on daily ICS 
maintenance therapy, defined as new or increased asthma symptoms (wheezing, coughing, 
dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that result 
in at least one of the following:
– Hospitalization or an emergency department or urgent care visit with systemic 
corticosteroid treatment
– Use of systemic (IV, IM, or oral) corticosteroids for 3 days or a long-acting depot 
corticosteroid preparation with a therapeutic effectiveness of 3 days 

Demonstration of acceptable inhaler, peak flow meter, and spirometry techniques at 
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
Demonstrated compliance with required use of the eDiary, defined as completing all 
required assessments (answering questions related to asthma symptoms, PEFR 
measurements, and use of short-acting rescue therapy) on at least 5 of 7 days during each 
of 2 consecutive weeks within the screening period (1228 days)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 60 days after the final dose of 
MTPS9579A.  
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.   If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 60 days after 
the final dose of MTPS9579A to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.  If required per local 
guidelines or regulations, information about the reliability of abstinence will be 
described in the local Informed Consent Form.
Inclusion Criteria for Enrollment in the Double-Blind Treatment Period
After completing the run-in period, patients must meet the following additional criteria for 
enrollment in the double-blind treatment period:

Ongoing compliance with required use of the eDiary, defined as completing all required 
assessments (answering questions related to asthma symptoms, PEFR measurements, 
and use of short-acting rescue therapy) on at least 5 of 7 days during each of the 
2 consecutive weeks of the run-in period 

No changes in ICS therapy or allowed controller medications during the run-in period 

No new asthma exacerbation or infection during the run-in period
Inclusion Criteria for the Optional Methacholine Challenge Test
Patients enrolled in the double-blind treatment period must meet the following additional criteria 
for enrollment into the optional methacholine challenge test:

Signed Informed Consent Form for the Optional Methacholine Challenge Test

Methacholine challenge at randomization (PD20200 g) 

FEV1 60%80% predicted


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Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History or evidence of vocal cord dysfunction, reactive airways dysfunction syndrome, 
hyperventilation associated with panic attacks, or other mimics of asthma

History or evidence of significant respiratory disease other than asthma, including 
occupational asthma, aspirin-sensitive asthma, asthma-chronic obstructive pulmonary 
disease (COPD) overlap syndrome, bronchiolitis, interstitial lung disease, or COPD 

Current smoker, electronic cigarette (e-cigarette) user, former smoker with smoking history 
of 10 pack-years, former e-cigarette user with an e-cigarette history of at least daily use 
for 10 years, or unwillingness to abstain from smoking and/or e-cigarette use from the 
time of consent through the completion of the study  
A current smoker is defined as someone who has smoked tobacco or marijuana 
products (by way of a cigarette, pipe, cigar, or e-cigarette) on at least 30 days within 
the 24 months prior to screening.
A patient who smokes or uses e-cigarettes occasionally (smoked or “vaped” a tobacco 
or marijuana product on fewer than 30 days within the 24 months prior to screening) 
and has a total smoking history of 10 pack-years may be permitted but must agree to 
abstain from all smoking or e-cigarette use during the study.
For e-cigarette users, no use of electronic cigarettes for at least 28 days prior to 
screening.

History or evidence of substance abuse that, in the investigator’s judgment, would affect the 
patient’s ability to participate in the study, pose a risk to patient safety, interfere with the
conduct of the study, or have an impact on the study results

History or evidence of any clinically significant medical condition/disease (e.g., psychiatric, 
neurologic, cardiovascular, renal, hepatic, gastrointestinal, endocrine, autoimmune) or 
abnormalities in laboratory tests that, in the investigator's judgment, precludes the patient’s 
safe participation and completion of the study, or interferes with the conduct and 
interpretation of the study
Patients with well-controlled comorbid disease on a stable treatment regimen for 
4 weeks prior to screening are eligible for the study.

Hemoglobin A1c (HbA1c) 8.5% at screening or any other clinically significant finding that, in 
the opinion of the investigator, may define uncontrolled diabetes

Myocardial infarction, unstable angina pectoris, or stroke within 12 months prior to 
screening

Any chronic heart failure exacerbation within 12 months prior to screening or at risk for 
heart failure exacerbation in the investigator’s opinion 

History or presence of an abnormal ECG that is clinically significant in the investigator's 
opinion, including complete left bundle branch block, second- or third-degree 
atrioventricular heart block, or evidence of prior myocardial infarction

QT interval corrected through use of Fridericia's formula (QTcF) 450 ms, if patient is male, 
or QTcF470, if patient is female, demonstrated by at least two ECGs 30 minutes apart

Active malignancy or history of malignancy within 5 years of screening, except for 
appropriately treated non-melanoma skin carcinoma, cervical carcinoma in situ, breast 
ductal carcinoma in situ, or Stage I uterine cancer

Positive for hepatitis C virus (HCV) antibody at screening, unless HCV RNA 15 IU/mL (or 
undetectable) at screening and for 6 months if successfully completed HCV anti-viral 
treatment

Positive hepatitis B surface antigen (HBsAg) at screening, or:
Negative HBsAg and positive hepatitis B core antibody (HBcAb); with a positive hepatitis B 
virus DNA test

Positive HIV antibody at screening


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
Positive for TB during screening, defined as either a positive purified protein derivative 
(PPD) test (5 mm of induration 4872 hours after injection) or a positive 
QuantiFERONTB Gold (QFT-G) test during screening
For patients with a history of bacille Calmette-Guérin (BCG) vaccination, the following 
criteria for the QFT-G apply:
– An indeterminate QFT-G should be repeated.
– A positive QFT-G or two successive indeterminate QFT-G results should be 
considered a positive diagnostic TB test.
– An indeterminate QFT-G followed by a negative QFT-G test should be considered a 
negative diagnostic TB test.
Patients with a positive PPD test or QFT-G are eligible if they meet all of the following 
criteria:
– No symptoms consistent with TB (see TB worksheet)
– Documented history of a completed course of adequate prophylaxis (completed 
treatment for latent TB per the treatment options as stated in the WHO guidelines) 
prior to screening
– No known exposure to a case of active TB after most recent prophylaxis
– No evidence of active TB on chest radiograph within 3 months prior to screening

Acute infection requiring either surgical intervention (e.g., drainage) or medical therapy 
(e.g., antibiotics) within 4 weeks prior to screening

Active parasitic infection within 6 months prior to screening

Planned surgical intervention during the course of the study

History of any known immunodeficiency disorder

History of documented immune complex disease (Type III hypersensitivity reactions) to 
monoclonal antibody administration

History of anaphylaxis to any biologic therapy for any indication

Known sensitivity to any of the active substances or their excipients to be administered 
during dosing

Initiation of or change in allergen immunotherapy within 3 months prior to screening, during 
the screening period, or anticipated need during the course of the study

Treatment with immunoglobulin or blood products within 4 weeks prior to screening, during 
the screening period, or anticipated need during the course of the study

Treatment with any live or live, attenuated vaccines within 4 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study  

Treatment with any licensed biologic agent (e.g., omalizumab, mepolizumab, reslizumab, 
dupilumab) within 3 months or 5 drug half-lives prior to screening (whichever is longer), 
during the screening period, or anticipated need during the course of the study

Treatment with any investigational therapy within 3 months or 5 drug half-lives prior to 
screening (whichever is longer), during the screening period, or anticipated need during the 
course of the study

Maintenance oral corticosteroid therapy, defined as daily or alternate day oral corticosteroid 
maintenance therapy, within 3 months prior to screening or during the screening period

Treatment with systemic corticosteroids within 4 weeks (oral or IV) or 12 weeks (IM) prior to 
screening or during the screening period for any reason, including treatment for an acute 
exacerbation event

Treatment with intra-articular corticosteroids within 4 weeks prior to screening, during the 
screening period, or anticipated need during the course of the study

Maintenance oral or SC -agonist therapy (e.g., terbutaline) within 2 weeks prior to 
screening, during the screening period, or anticipated need during the course of the study


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
Treatment with phosphodiesterase-4 inhibitors (e.g., roflumilast) within 4 weeks prior to 
screening, during the screening period, or anticipated need during the course of the study

Treatment with immunomodulatory, immunosuppressive (e.g., methotrexate, 
troleandomycin, oral gold, cyclosporine, azathioprine), or experimental anti-inflammatory 
therapy within 3 months or 5 drug half-lives prior to screening (whichever is longer), during 
the screening period, or anticipated need for these medications during the course of the 
study

Maintenance oral or inhaled antibiotic therapy within 2 weeks prior to screening, during the 
screening period, or anticipated need during the course of the study

Treatment with mast cell stabilizers (e.g., chromolyn) within 2 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study

Treatment with homeopathic medications, herbal medications, acupuncture, or hypnosis for 
treatment of allergic disease within 2 weeks prior to screening, during the screening period, 
or anticipated need during the course of the study

Intubation for respiratory failure due to asthma within 12 months prior to screening

Maintenance intermittent positive pressure ventilation within 2 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study

Maintenance bilevel positive airway pressure therapy within 2 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study

Bronchial thermoplasty treatment within 24 months prior to screening, during the screening 
period, or anticipated need during the course of the study

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
60 days after the final dose of MTPS9579A
Women of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test result at the randomization visit.
End of Study
The end of this study is defined as the date when all patients have completed the study 
completion or early termination visit, or have otherwise been discontinued from the study.  The 
total duration of this study for each patient is approximately 62 weeks, including screening, 
run-in, treatment, and follow-up.
In addition, the Sponsor may decide to terminate enrollment or the entire study at any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 25 months. 
Investigational Medicinal Products
MTPS9579A and Placebo
During the run-in period, patients will receive one single-blind dose of placebo (Week 0) to allow 
for evaluation of variability in asthma control.  During the double-blind treatment period, 
MTPS9579A or placebo will be administered by IV infusion at the randomization visit (Week 2), 
Week 6, and every 4 weeks thereafter through Week 46.
Non-Investigational Medicinal Products
Methacholine is considered a non-investigational medicinal product (NIMP) for this study as it is 
a bronchial challenge agent.  All patients must be on a stable asthma treatment regimen 
consisting of ICS therapy plus at least one additional controller medication.  Refer to the local 
prescribing information for the formulation, packaging, and handling of these medications.  
Patients may not be on systemic (oral, IV, or IM) corticosteroids, biologic agents, or 
experimental therapeutics for the treatment of asthma (see the protocol for details).






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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACQ-5
Asthma Control Questionnaire, 5-item version 
ADA
anti-drug antibody
ATS
American Thoracic Society
BCG
bacille Calmette-Guérin
CompEx
composite of diary events and asthma exacerbations 
(endpoint)
COPD
chronic obstructive pulmonary disease
DAP
Data Analysis Plan
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
eDiary
electronic diary
ERS
European Respiratory Society
FDA
Food and Drug Administration
FeNO
fractional exhaled nitric oxide
FEV1
forced expiratory volume in 1 second 
FVC
forced vital capacity 
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
ICS
inhaled corticosteroids
IL
interleukin
IM
intramuscular
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LABA
long-acting -agonist
LAMA
long-acting muscarinic antagonist
LTM
leukotriene modifier
LTRA
leukotriene receptor antagonist


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Abbreviation
Definition
MAD
multiple ascending dose
mITT
modified intent-to-treat
NGS
next-generation sequencing
PD20
provocative dose of methacholine producing a 20% 
drop in FEV1
PD
pharmacodynamic
PEFR
peak expiratory flow rate
PFT
pulmonary function testing
PK
pharmacokinetic
PPD
purified protein derivative
PRO
patient-reported outcome
Q4W
every 4 weeks
QFT-G
QuantiFERON® TB Gold (test)
QTcF
QT interval corrected through use of Fridericia's 
formula
RBR
Research Biosample Repository
SABA
short-acting -agonist
SAD
single ascending dose
SAMA
short-acting muscarinic antagonist
TB
tuberculosis
ULN
upper limit of normal
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON ASTHMA
Asthma is a chronic inflammatory disease of the airways with an increasing worldwide 
incidence (To et al. 2012).  Approximately 420,000 people die each year as a result of 
asthma (Global Asthma Network 2018).  The pathophysiology of the disease is 
characterized by variable airflow obstruction, airway inflammation, mucus 
hypersecretion, and subepithelial fibrosis (NHLBI 2007).  Clinically, patients may present 
with cough, wheezing, and shortness of breath.  Despite the development of effective 
controller therapies for asthma—such as inhaled corticosteroids (ICS), long-acting -
agonists (LABA), and other controller medications—a substantial proportion of patients 
continue to have uncontrolled symptoms, airflow obstruction, and exacerbations 
(Bateman et al. 2004; Peters et al. 2006; CDC 2014).  Development of new therapies is 
needed for patients with asthma that remains uncontrolled despite standard-of-care 
therapies. 
Substantial evidence indicates that asthma is not a uniform condition, and there is 
considerable heterogeneity in clinical characteristics, severity of disease, and underlying 
biology.  The best characterized subtypes consist of those patients in whom the disease 
is driven by IgE and cytokines expressed by mast cells, type 2 T-helper cells, and type 2 
innate lymphoid cells, namely interleukin (IL)-4, IL-5, and IL-13; allergic disease and 
peripheral eosinophilia are common features.  Tryptase is the most abundant secretory 
granule protein in human lung mast cells and is secreted from mast cells upon activation 
during inflammatory or allergic responses (Zhang and Timmerman 1997; Payne and 
Kam 2004).  Tryptase is a serine protease and is enzymatically active only in the 
tetrameric form.  Tetrameric tryptase is assembled in the mast cell granule in the 
presence of heparin and an acidic environment and is released upon mast cell 
activation/degranulation.  Catalytically active extracellular secreted tryptase promotes 
airway hyper-responsiveness, bronchoconstriction, and amplification of mast cell 
degranulation (Sommerhoff 2001; He et al. 2004; Bradding and Arthur 2016).  
Tryptase levels are elevated in bronchial alveolar lavage fluid and serum of patients with 
asthma, and correlate with disease severity.  Loss-of-function mutations in genes 
encoding tryptases (TPSAB1 and TPSB2) are common in ethnically diverse populations.  
These mutations correlate with tryptase activity in vitro, total peripheral tryptase levels in 
patients with moderate to severe asthma, and clinical response to treatment with the 
anti-IgE antibody omalizumab (Choy et al. 2018).  As these mutations determine 
expression of functional tryptase, they may predict clinical outcomes for inhibitors of 
tryptase activity.  Multiple small molecule inhibitors blocking tryptase function have 
shown efficacy in rodent and sheep models of allergic asthma (Clark et al. 2001).  
In addition, a small molecule inhibitor of tryptase, APC 366, has been shown to exhibit 
clinical activity by attenuating inhaled allergen-induced late asthmatic response in 
patients with mild atopic asthma (Krishna et al. 2001).


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1.2
BACKGROUND ON MTPS9579A
MTPS9579A is a full-length humanized IgG4 antibody that binds with high affinity to 
human and cynomolgus monkey tryptase.  MTPS9579A inhibits tryptase activity by 
irreversibly dissociating the active tetramer into inactive monomers.  MTPS9579A is 
currently under clinical investigation in a Phase Ia/b dose-escalation trial (GA40396) in 
approximately 106 healthy volunteers.  The dose has been escalated in both single 
ascending dose (SAD) and multiple ascending dose (MAD) cohorts up to a maximum of 
3600 mg IV for SAD or MAD (every 4 weeks [Q4W] for 3 doses).  In addition, a Phase Ic 
study is planned to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) 
relationships of MTPS9579A in the lung using bronchoscopy in patients with asthma 
after a single dose.  MTPS9579A has been well tolerated at all dose levels, with no 
serious adverse events and only one adverse event leading to discontinuationa 
volunteer who developed Grade 2 increased blood creatine phosphokinase.  All reported 
adverse events in 106 healthy volunteers have been Grade 1 or 2, and most events 
resolved without requiring treatment.  After administration of MTPS9579A in these 
healthy volunteers, active tryptase measurements from the nasal mucosal lining fluid 
decreased below detection levels.  Greater than 95% target inhibition is anticipated in 
patients with asthma at the proposed dose of 1800 mg IV Q4W.
Refer to the MTPS9579A Investigator's Brochure for details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The rationale for conducting this Phase IIa proof-of-activity study of MTPS9579A in 
patients with asthma requiring ICS and a second controller is to evaluate efficacy, safety, 
pharmacokinetics, and pharmacodynamics in a relevant patient population.  Inhibiting 
tryptase with MTPS9579A is anticipated to block airway inflammation downstream of 
mast cell activation across all asthma types.  The goals of this study are to determine the
impact of monthly treatment with MTPS9579A on patients’ signs and symptoms of 
asthma using a combination of patient-reported measures and functional measures of 
exacerbation and to continue to understand safety and the PK/PD relationships of 
MTPS9579A and tryptase.
The safety profile of MTPS9579A in healthy volunteers from the Phase Ia/b study 
(GA40396) is described in Section 1.2 and in the MTPS9579A Investigator’s Brochure.  
Risks in patients with asthma are unknown, but the favorable safety profile in healthy 
volunteers supports further development in patients with asthma.  The safety plan for 
patients in this study is described in Section 5.1.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of MTPS9579A
compared with placebo in patients with uncontrolled asthma despite the use of ICS and 


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a second controller.  Specific objectives and corresponding endpoints for the study are 
outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of MTPS9579A 
compared with placebo on the basis of the following endpoint:

Time to first CompEx event (Fuhlbrigge et al. 2017), a composite endpoint defined 
as time from randomization to first asthma exacerbation or diary worsening during 
the 48-week double-blind treatment period (from the randomization visit [Week 2] to 
end of treatment [Week 50]).  Asthma exacerbations and diary worsening are 
defined as follows: 
Asthma exacerbations are assessed by the investigator and defined as new or 
increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/ 
or nighttime awakenings due to these symptoms) that result in one or both of the 
following:
–
Hospitalization or an emergency department or urgent care visit requiring 
administration of systemic corticosteroid treatment
–
Treatment with systemic (IV, intramuscular [IM], or oral) corticosteroids for 
3 days or a long-acting depot corticosteroid preparation with a 
therapeutic effectiveness of 3 days

Diary worsening is based on the occurrence of prespecified changes (deteriorations) 
in a subset of the following six parameters:  morning peak expiratory flow rate 
(PEFR), evening PEFR, morning symptom score, evening symptom score, morning 
short-acting rescue therapy use, and evening short-acting rescue therapy use.  A 
detailed definition of diary worsening is provided in Section 6.4.1.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of MTPS9579A 
compared with placebo on the basis of the following endpoints:

Rate of asthma exacerbations (as defined in primary efficacy objective and 
assessed by the investigator) during the 48-week double-blind treatment period

Time to first asthma exacerbation during the 48-week double-blind treatment period

Absolute and relative change from randomization in pre-bronchodilator forced 
expiratory volume in 1 second (FEV1; liters) at Week 50

Absolute and relative change from randomization in fractional exhaled nitric oxide
(FeNO) at Week 50


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2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of 
MTPS9579A compared with placebo on the basis of the following endpoints:

Rate of severe asthma exacerbations during the 48-week double-blind treatment 
period, defined as asthma symptoms requiring hospitalization or resulting in death 
attributed to asthma

Absolute change from randomization in pre-bronchodilator FEV1 (percentage 
predicted) at Week 50

Absolute change from randomization in patient-reported daytime asthma symptom 
severity, as measured by a daily symptom diary (as defined in primary efficacy 
objective), at Week 50

Absolute change from randomization in patient-reported nighttime asthma symptom 
severity, as measured by a daily symptom diary (as defined in primary efficacy 
objective), at Week 50

Absolute change from randomization in patient-reported number of puffs of short-
acting rescue inhaler or number of times nebulizer was used at Week 50

Absolute and relative change from randomization visit in provocative dose of 
methacholine causing a 20% drop in FEV1 (PD20) as a measure of airway hyper-
responsiveness at Week 30, in patients who consent to this optional assessment at 
select sites
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of MTPS9579A compared 
with placebo on the basis of the following endpoints:

Incidence and severity of adverse events, with severity determined according to the 
WHO Toxicity Grading Scale

Change from randomization visit in physical examination findings 

Change from randomization visit in vital signs 

Change from randomization visit in ECG parameters 

Change from randomization visit in clinical laboratory results
2.3
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the MTPS9579A PK profile on the basis 
of the following endpoint:

Serum concentration of MTPS9579A at specified timepoints
The exploratory PK objective for this study is to characterize concentrations of 
MTPS9579A in nasal mucosal lining fluid and to evaluate potential relationships between 


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drug exposure and the efficacy and safety of MTPS9579A on the basis of the following 
endpoints:

Relationship between serum concentration, nasal mucosal lining fluid concentration, 
or PK parameters for MTPS9579A and efficacy or PD endpoints

Relationship between serum concentration, nasal mucosal lining fluid concentration, 
or PK parameters for MTPS9579A and safety endpoints
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
MTPS9579A on the basis of the following endpoint:

Prevalence of anti-drug antibodies (ADAs) during the study relative to the 
prevalence of ADAs at the randomization visit
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK/PD endpoints
2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to MTPS9579A (i.e., predictive biomarkers), 
can provide evidence of MTPS9579A activity (i.e., PD biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of the 
following endpoints:

Change from the randomization visit in biomarker levels in nasal mucosal lining 
fluid, urine, and serum samples

Relationship among biomarker levels in nasal mucosal lining fluid, urine, and serum 
samples

Relationship between biomarkers in nasal mucosal lining fluid, urine, and serum 
(listed in Section 4.5.9) and efficacy, safety, PK, and immunogenicity endpoints

Rate of asthma exacerbations within subgroups defined by blood eosinophils during 
the 48-week double-blind treatment period

Time to first CompEx event (as defined in primary efficacy objective) within 
subgroups defined by blood eosinophils during the 48-week double-blind treatment 
period

Rate of asthma exacerbations in subgroups defined by mutations in the genes 
encoding tryptase (TPSAB1 and TPSB2) during the 48-week double-blind treatment 
period

Time to first CompEx event (as defined in primary efficacy objective) in subgroups 
defined by mutations in the genes encoding tryptase (TPSAB1 and TPSB2) during 
the 48-week double-blind treatment period


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3.
STUDY DESIGN
3.1
OVERVIEW OF THE STUDY DESIGN
This is a Phase IIa, randomized, placebo-controlled, double-blind, multicenter, two-arm 
study of MTPS9579A compared with placebo as an add-on therapy in patients with 
uncontrolled moderate to severe asthma who are receiving daily ICS therapy and at 
least one of the following additional controller medications:  LABA, leukotriene modulator 
(leukotriene modifier [LTM] or leukotriene receptor antagonist [LTRA]), long-acting 
muscarinic antagonist (LAMA), or long-acting theophylline preparation.  The study 
initially was to randomize approximately 160 patients at approximately 55 sites globally.
However, as of March 2021, study enrollment was halted with 134 patients enrolled,
and in August 2021, a decision was made to permanently halt further enrollment.
This study will consist of a 1228 day screening period, a 2-week single-blind placebo 
run-in period, a 48-week double-blind treatment period, a safety follow-up visit at 
Week 54, and a safety follow-up phone call at Week 58.  During the screening period, 
patients must demonstrate acceptable inhaler, peak flow meter, and spirometry 
techniques, in addition to compliance with required, twice-daily use of an electronic diary 
(eDiary) for answering questions related to asthma symptoms, PEFR, and short-acting 
rescue therapy use (see Section 4.5.8).  Patients who fail to meet eligibility criteria 
during the screening period will be permitted to re-screen once as described in 
Section 3.1.1.  
Patients who meet enrollment criteria for the run-in period will receive one single-blind 
dose of placebo (Week 0) to allow for the evaluation of variability in asthma control.  At 
the randomization visit (Week 2), patients must meet additional eligibility criteria for the 
double-blind treatment period that includes continued compliance with required, twice-
daily use of the eDiary (see Section 4.1.1.2).  
Patients will be randomized in a 1:1 ratio to receive MTPS9579A (1800 mg IV Q4W) or 
placebo as described in Section 4.2.  Study drug will be administered by IV infusion at 
the randomization visit (Week 2), Week 6, and every 4 weeks thereafter through 
Week 46.
During the treatment period, twice-daily assessment of asthma-related symptoms, 
PEFR, and use of short-acting rescue therapy (see Section 4.5.8) will continue to be 
performed at home and recorded in the eDiary.  More detailed assessments, including 
spirometry and FeNO measurements, will be performed during scheduled site visits.  All 
patients will undergo PK, biomarker, and ADA sampling.  An additional exploratory 
efficacy assessment, the methacholine challenge test to assess airway reactivity, will be 
conducted at select sites in a subset of patients (approximately 20 patients/study arm) 
who consent to this option and meet additional eligibility criteria (see 
Sections 4.1.1.3 and 4.5.14). 


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A planned interim analysis will take place once approximately 51 patients have 
experienced a CompEx event in the 48-week, double-blind treatment period.  The 
expected timing of this planned interim analysis is approximately 60 weeks after the first 
patient is randomized.  An optional interim analysis may also be conducted.  These
interim analyses will be conducted for potential enrollment decisions (e.g., temporary or 
permanent enrollment halt, change to number of total randomized patients), for early 
study termination, or for administrative purposes (e.g., planning of future studies) (see 
Section 6.9).
Figure 1 presents an overview of the study design.  A schedule of activities is provided in
Appendix 1.


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Figure 1
Study Schema
EOSend of study; EOT end of treatment; F/Usafety follow-up; ICSinhaled corticosteroids; T/Ctelephone call; Q4W every 4 weeks.
a Screening period is 1228 days.


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3.1.1
Screening Period
The screening period of up to 4 weeks is intended to allow sufficient time for a patient to 
meet all eligibility requirements.  Patients must complete at least 12 days of the 
screening period to demonstrate eDiary compliance (see Section 4.1.1.1).  Patients who 
are unable to complete assessments or meet eligibility requirements during the 
screening period will be permitted to be re-screened once for a total of up to two times. 
Within a screening period, patients who do not meet the requirement of 
pre-bronchodilator FEV1 of 40%80% or post-bronchodilator reversibility of FEV1 (liters) 
of 12% and 200 mL are allowed up to two additional attempts to meet these two 
eligibility criteria, but only if their pre-bronchodilator FEV1 was between 35% and 85%.  
Patients who rescreen 6 weeks after Informed Consent Form completion must only 
repeat the assessments that triggered screen failure.  Patients who rescreen 6 weeks 
after Informed Consent Form completion are required to repeat the consent process and 
all screening assessments except tuberculosis (TB) screening and hepatitis serologies.  
However, TB screening and hepatitis serologies should be repeated if the re-screening 
takes place 6 months after initial screening or if there is risk of exposure.
3.1.2
Run-In Period
Patients enrolled in the run-in period will receive one single-blind dose of placebo at the 
run-in visit (Week 0).  eDiary compliance must continue to be demonstrated on at least 
5 of 7 days during each of the 2 consecutive weeks of the run-in period (see 
Section 4.1.1.2).  Patients who do not meet eligibility criteria for the double-blind 
treatment period will be discontinued from the study and are not eligible for rescreening 
(see Section 4.6.2).  
3.1.3
Internal Monitoring Committee
Periodic safety reviews will be performed by the Sponsor’s Internal Monitoring 
Committee (IMC) as outlined in the IMC Charter.  This committee will be unblinded to 
treatment assignments and will include a clinical scientist, drug safety scientist, 
biostatistician, and statistical programmer from the Sponsor.  The IMC members will not 
have direct contact with investigational staff or site monitors.  The IMC may decide to 
unblind the study team to enable decision-making.  The IMC may invite representatives 
from other functional areas on an ad-hoc basis when additional expertise is required 
(e.g., clinical pharmacology, research) or invite additional Sponsor scientists to 
participate in data analyses and review. 
The IMC will meet at a frequency dictated by the IMC charter but no less frequently than 
once every 3 months. Additionally, ad-hoc IMC meetings may be convened immediately 
or expeditiously at any time to address potential safety concerns if periodic review of 
blinded safety data indicates 3 or more patients with serious or Grade 3 or higher 
adverse events (excluding asthma exacerbations) that the investigator or Sponsor 
determines to be related to study treatment, within the same MedDRA high level term. 


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The IMC will assess the severity, relatedness, and reversibility of adverse events, the 
degree of imbalance between treatment arms, the similarity and frequency of events 
under a single higher level term, the plausibility of a common mechanism, possible risk 
mitigation measures, and may recommend changes to study conduct (including 
termination of study) as appropriate.
At any time during the study, the Sponsor may choose to inactivate and suspend 
enrollment and further dosing or reduce the dose due to safety concerns as 
recommended by the IMC. Should an ad-hoc IMC meeting be convened, enrollment of 
patients may be temporarily halted if warranted by the frequency and severity of the 
blinded adverse events, until the IMC evaluates the unblinded data and decides whether 
resumption of dosing is safe to proceed, or until IMC-recommended changes to the 
conduct of the study are implemented. 
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when all patients have completed the study 
completion or early termination visit, or have otherwise been discontinued from the 
study.  The total duration of this study for each patient is approximately 62 weeks, 
including screening, run-in, treatment, and follow-up.
In addition, the Sponsor may decide to terminate enrollment or the entire study at any 
time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 25 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for MTPS9579A Dose and Schedule
The dose of MTPS9579A in this study (1800 mg IV Q4W) has been selected by the 
Sponsor based on the totality of the following data: understanding of tryptase biology in 
healthy volunteers and patients with asthma, Phase Ia/b SAD/MAD clinical trial data, 
MTPS9579A properties, mechanism of action, nonclinical activity and safety, and prior 
clinical experience targeting tryptase.  The selected Phase IIa dose is within the dose 
range previously evaluated in the Phase Ia/b study (GA40396).  In that study, doses up 
to 3600 mg of MTPS9579A administered intravenously as a single dose or as a Q4W 
regimen (3 doses), which was the maximum dose tested, was well tolerated.  The dose 
and regimen to be tested in this study (1800 mg IV Q4W) is projected to maximize the 
potential for clinical benefit based on the totality of data available to date.  At steady-
state concentrations, it is anticipated that this dose will reduce active tryptase levels by 
95%, which accounts for the maximum concentration of active tryptase that may be 
present in the airway of patients with asthma while ensuring patient safety.  More details 
on the safety, PK, and PD activity of MTPS9579A are available in the MTPS9579A 
Investigator’s Brochure.


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3.3.2
Rationale for Patient Population
The current high unmet medical need in asthma is for patients with uncontrolled 
disease despite adherence to guidelines-based, standard-of-care therapy.  In this study, 
the target population is patients with moderate to severe asthma whose disease 
remains uncontrolled despite daily use of ICS therapy and at least one additional 
controller medication.  Patients must have a diagnosis of asthma, an Asthma Control 
Questionnaire, 5-item version (ACQ-5) score 1.5 (Appendix 2), and have experienced 
at least two asthma exacerbations (as defined in Section 4.1.1.1) within the 12 months 
prior to screening as evidence of uncontrolled disease.
Patients with uncontrolled asthma despite treatment represent a high unmet medical 
need because they have exhausted conventional therapeutic options.  A recent study 
has demonstrated that patients with a history of exacerbations are at the highest risk for 
future exacerbations (Bloom et al. 2018).  Therapeutic options for these patients are 
limited because of the heterogeneity of clinical response to controller medications and 
the substantial side effects of high-dose ICS and oral corticosteroid therapy (Wong et al. 
2000; Holt et al. 2001; Suissa et al. 2002; Szefler et al. 2002; Masoli et al. 2004a, 2004b, 
2005; Adams and Jones 2006; Sears et al. 2009; Lemanske et al. 2010). 
The National Heart, Lung, and Blood Institute Expert Panel Report 3 (2007) and Global 
Initiative for Asthma (2018) guidelines include several options for the addition of 
controller medications, including LAMAs (e.g., tiotropium), which reflect the 
heterogeneity of clinical response to each medication class (Lemanske et al. 2010).  
Consequently, the protocol-defined additional controller medications include LABAs, 
LTM/LTRAs, and LAMAs.  While individuals in this population with eosinophilic asthma 
respond favorably to treatment with biologic-based therapies modulating eosinophil-
related signaling pathways (IL-5, IL-4/IL-13), these therapies are of limited benefit to 
patients with asthma who have lower levels of eosinophils.
3.3.3
Rationale for Control Group
A placebo-treated control group will be used in this study to assess differences in 
CompEx events, pulmonary function, asthma control, symptoms, PD biomarkers, and 
safety in patients who receive MTPS9579A compared with patients who receive 
placebo.  The use of a control group is necessary to assess safety signals that may be 
attributable to MTPS9579A in a patient population and given the inherent variability in 
symptoms and lung function.  Patients in the control group will undergo the same study 
assessments as patients treated with MTPS9579A.  All patients will continue to receive 
standard-of-care treatment for asthma and other allowable medical conditions (with 
some restrictions; refer to Section 4.4) in addition to study drug (MTPS9579A or 
matching placebo) throughout the study.


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3.3.4
Rationale for Biomarker Assessments
Biomarker assessments, before and at various timepoints after treatment, will be used to 
demonstrate evidence of the biologic activity of MTPS9579A in patients, identify 
biomarkers that may be predictive of response to MTPS9579A, define PK/PD 
relationships, support selection of a recommended dose regimen, advance the 
understanding of the mechanism of action of MTPS9579A in patients, and increase the 
knowledge and understanding of disease biology.  During this study, urine samples, 
serum samples, blood samples, and upper airway samples will be collected.  
Nasosorption is an upper airway, non-invasive sampling method that uses a synthetic 
absorptive matrix to collect nasal mucosal lining fluid from the nose.
Blood samples will be collected for DNA extraction to enable identification of mutations 
in genes encoding tryptase (TPSAB1 and TPSB2) that are associated with tryptase 
levels and activity in the airway or can increase the knowledge and understanding of 
disease biology.
3.3.5
Rationale for Optional Methacholine Challenge Test
Mast cell microlocalization within airway smooth muscle cell bundles is thought to 
contribute to airway hyper-responsiveness (Brightling et al. 2002).  Methacholine 
challenge testing, a measure of airway hyper-responsiveness, will be used to 
demonstrate physiological activity of MTPS9579A in patients.  This assay will be 
examined with PK/PD and biomarker data to understand the mechanism of action of 
MTPS9579A.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 160 patients with moderate to severe asthma were originally planned to
be randomized in this study (80 patients in each of 2 treatment arms); however, as of
August 2021, study enrollment has been halted with 134 patients enrolled.
4.1.1
Inclusion Criteria
4.1.1.1
Inclusion Criteria for Enrollment in the Run-In Period
Patients must meet the following criteria for enrollment in the run-in period:

Signed Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Age 1875 years, inclusive, at the time of signing the Informed Consent Form

Body mass index of 1838 kg/m2 and weight 40 kg at screening

Documented physician-diagnosed asthma for at least 12 months prior to screening

Pre-bronchodilator FEV1 40%80% predicted at screening 


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
Post-bronchodilator reversibility of FEV1 (liters) 12% and 200 mL at screening
Post-bronchodilator reversibility testing, including medication-withholding 
strategies and appropriate dosing of short-acting bronchodilators, should be 
performed per American Thoracic Society (ATS)/European Respiratory Society 
(ERS) guidelines (Miller et al. 2005).
Alternative evidence demonstrating variable expiratory airway limitation may be 
considered after discussion with the Medical Monitor.

Treatment with asthma controller therapy (daily ICS [100 g of fluticasone 
propionate or equivalent] and at least one additional controller therapy [LABA, 
LAMA, LTM/LTRA]) for 3 months prior to screening, with no changes within 
4 weeks prior to screening or during the screening period and no anticipated 
changes in controller dosing regimens throughout the study
For patients receiving a total daily ICS dose of 500 g fluticasone propionate 
or equivalent, one of their additional controller therapies must be LABA.
For patients receiving a total daily ICS dose of 500 g fluticasone propionate 
or equivalent, they must receive one or more of the following additional 
controller therapies:  LABA, LTM/LTRA, LAMA, or long-acting theophylline 
preparations.

ACQ-5 score 1.5 at screening

Documented history (e.g., medical report, pharmacy prescription assessed by 
investigator) of 2 asthma exacerbations within the 12 months prior to screening 
while on daily ICS maintenance therapy, defined as new or increased asthma 
symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime 
awakenings due to these symptoms) that result in at least one of the following:
–
Hospitalization or an emergency department or urgent care visit with systemic 
corticosteroid treatment
–
Use of systemic (IV, IM, or oral) corticosteroids for 3 days or a long-acting 
depot corticosteroid preparation with a therapeutic effectiveness of 3 days

Demonstration of acceptable inhaler, peak flow meter, and spirometry techniques at 
screening

Demonstrated compliance with required use of the eDiary, defined as completing all 
required assessments (answering questions related to asthma symptoms, PEFR 
measurements, and use of short-acting rescue therapy) on at least 5 of 7 days 
during each of 2 consecutive weeks within the screening period (1228 days)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 60 days after the final dose 
of MTPS9579A.  
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 


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amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  If 
required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
60 days after the final dose of MTPS9579A to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form.
4.1.1.2
Inclusion Criteria for Enrollment in the Double-Blind Treatment 
Period
After completing the run-in period, patients must meet the following additional criteria for 
enrollment in the double-blind treatment period:

Ongoing compliance with required use of the eDiary, defined as completing all 
required assessments (answering questions related to asthma symptoms, PEFR 
measurements, and use of short-acting rescue therapy) on at least 5 of 7 days 
during each of the 2 consecutive weeks of the run-in period 

No changes in ICS therapy or allowed controller medications (see Section 4.1.1.1) 
during the run-in period 

No new asthma exacerbation or infection (defined in Section 4.1.2) during the run-in 
period


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4.1.1.3
Inclusion Criteria for the Optional Methacholine Challenge Test
Patients enrolled in the double-blind treatment period must meet the following additional 
criteria for enrollment into the optional methacholine challenge test:

Signed Informed Consent Form for the Optional Methacholine Challenge Test

Methacholine challenge at randomization (PD20200 g) 

FEV1 60%80% predicted
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History or evidence of vocal cord dysfunction, reactive airways dysfunction 
syndrome, hyperventilation associated with panic attacks, or other mimics of asthma

History or evidence of significant respiratory disease other than asthma, including 
occupational asthma, aspirin-sensitive asthma, asthma-chronic obstructive 
pulmonary disease (COPD) overlap syndrome, bronchiolitis, interstitial lung disease, 
or COPD 

Current smoker, electronic cigarette (e-cigarette) user, former smoker with smoking 
history of 10 pack-years, former e-cigarette user with an e-cigarette history of at 
least daily use for 10 years, or unwillingness to abstain from smoking and/or 
e-cigarette use from the time of consent through the completion of the study  
A current smoker is defined as someone who has smoked tobacco or marijuana 
products (by way of a cigarette, pipe, cigar, or e-cigarette) on at least 30 days 
within the 24 months prior to screening.
A patient who smokes or uses e-cigarettes occasionally (smoked or “vaped” a 
tobacco or marijuana product on fewer than 30 days within the 24 months prior 
to screening) and has a total smoking history of 10 pack-years may be 
permitted but must agree to abstain from all smoking or e-cigarette use during 
the study.
For e-cigarette users, no use of electronic cigarettes for at least 28 days prior to 
screening.

History or evidence of substance abuse that, in the investigator’s judgment, would 
affect the patient’s ability to participate in the study, pose a risk to patient safety, 
interfere with the conduct of the study, or have an impact on the study results

History or evidence of any clinically significant medical condition/disease (e.g., 
psychiatric, neurologic, cardiovascular, renal, hepatic, gastrointestinal, endocrine, 
autoimmune) or abnormalities in laboratory tests that, in the investigator's judgment, 
precludes the patient’s safe participation and completion of the study, or interferes 
with the conduct and interpretation of the study
Patients with well-controlled comorbid disease on a stable treatment regimen 
for 4 weeks prior to screening are eligible for the study.

Hemoglobin A1c (HbA1c) 8.5% at screening or any other clinically significant finding 
that, in the opinion of the investigator, may define uncontrolled diabetes


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
Myocardial infarction, unstable angina pectoris, or stroke within 12 months prior to 
screening

Any chronic heart failure exacerbation within 12 months prior to screening or at risk 
for heart failure exacerbation in the investigator’s opinion 

History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, second- or 
third-degree atrioventricular heart block, or evidence of prior myocardial infarction

QT interval corrected through use of Fridericia's formula (QTcF) 450 ms, if patient 
is male, or QTcF470, if patient is female, demonstrated by at least two ECGs 
30 minutes apart

Active malignancy or history of malignancy within 5 years of screening, except for 
appropriately treated non-melanoma skin carcinoma, cervical carcinoma in situ, 
breast ductal carcinoma in situ, or Stage I uterine cancer

Positive for hepatitis C virus (HCV) antibody at screening, unless HCV RNA 
15 IU/mL (or undetectable) at screening and for 6 months if successfully 
completed HCV anti-viral treatment

Positive hepatitis B surface antigen (HBsAg) at screening, or:
Negative HBsAg and positive hepatitis B core antibody (HBcAb); with a positive 
hepatitis B virus (HBV) DNA test

Positive HIV antibody at screening

Positive for TB during screening, defined as either a positive purified protein 
derivative (PPD) test (5 mm of induration 4872 hours after injection) or a positive 
QuantiFERONTB Gold (QFT-G) test during screening
For patients with a history of bacille Calmette-Guérin (BCG) vaccination, the 
following criteria for the QFT-G apply:
–
An indeterminate QFT-G should be repeated.
–
A positive QFT-G or two successive indeterminate QFT-G results should be 
considered a positive diagnostic TB test.
–
An indeterminate QFT-G followed by a negative QFT-G test should be 
considered a negative diagnostic TB test.
Patients with a positive PPD test or QFT-G are eligible if they meet all of the 
following criteria:
–
No symptoms consistent with TB (see TB worksheet; Appendix 3)
–
Documented history of a completed course of adequate prophylaxis 
(completed treatment for latent TB per the treatment options as stated in 
the WHO guidelines; WHO 2018) prior to screening
–
No known exposure to a case of active TB after most recent prophylaxis
–
No evidence of active TB on chest radiograph within 3 months prior to 
screening


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
Acute infection requiring either surgical intervention (e.g., drainage) or medical 
therapy (e.g., antibiotics) within 4 weeks prior to screening

Active parasitic infection within 6 months prior to screening

Planned surgical intervention during the course of the study

History of any known immunodeficiency disorder

History of documented immune complex disease (Type III hypersensitivity reactions) 
to monoclonal antibody administration

History of anaphylaxis to any biologic therapy for any indication

Known sensitivity to any of the active substances or their excipients to be 
administered during dosing

Initiation of or change in allergen immunotherapy within 3 months prior to screening, 
during the screening period, or anticipated need during the course of the study

Treatment with immunoglobulin or blood products within 4 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study

Treatment with any live or live, attenuated vaccines within 4 weeks prior to 
screening, during the screening period, or anticipated need during the course of the 
study  

Treatment with any licensed biologic agent (e.g., omalizumab, mepolizumab, 
reslizumab, dupilumab) within 3 months or 5 drug half-lives prior to screening 
(whichever is longer), during the screening period, or anticipated need during the 
course of the study

Treatment with any investigational therapy within 3 months or 5 drug half-lives prior 
to screening (whichever is longer), during the screening period, or anticipated need 
during the course of the study

Maintenance oral corticosteroid therapy, defined as daily or alternate day oral 
corticosteroid maintenance therapy, within 3 months prior to screening or during the 
screening period

Treatment with systemic corticosteroids within 4 weeks (oral or IV) or 12 weeks (IM) 
prior to screening or during the screening period for any reason, including treatment 
for an acute exacerbation event

Treatment with intra-articular corticosteroids within 4 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study

Maintenance oral or SC -agonist therapy (e.g., terbutaline) within 2 weeks prior to 
screening, during the screening period, or anticipated need during the course of the 
study

Treatment with phosphodiesterase-4 inhibitors (e.g., roflumilast) within 4 weeks prior 
to screening, during the screening period, or anticipated need during the course of 
the study

Treatment with immunomodulatory, immunosuppressive (e.g., methotrexate, 
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inflammatory therapy within 3 months or 5 drug half-lives prior to screening 
(whichever is longer), during the screening period, or anticipated need for these 
medications during the course of the study

Maintenance oral or inhaled antibiotic therapy within 2 weeks prior to screening, 
during the screening period, or anticipated need during the course of the study

Treatment with mast cell stabilizers (e.g., chromolyn) within 2 weeks prior to 
screening, during the screening period, or anticipated need during the course of the 
study

Treatment with homeopathic medications, herbal medications, acupuncture, or 
hypnosis for treatment of allergic disease within 2 weeks prior to screening, during 
the screening period, or anticipated need during the course of the study

Intubation for respiratory failure due to asthma within 12 months prior to screening

Maintenance intermittent positive pressure ventilation within 2 weeks prior to 
screening, during the screening period, or anticipated need during the course of the 
study

Maintenance bilevel positive airway pressure therapy within 2 weeks prior to 
screening, during the screening period, or anticipated need during the course of the 
study

Bronchial thermoplasty treatment within 24 months prior to screening, during the 
screening period, or anticipated need during the course of the study

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 60 days after the final dose of MTPS9579A
Women of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test result at the randomization visit.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After successful completion of the run-in period, at the Week 2 visit, patients will be 
randomly allocated to treatment with MTPS9579A or placebo at a 1:1 ratio through an 
interactive voice or web-based response system (IxRS).  Randomization will be stratified 
by region (United States/Western Europe vs. Eastern Europe vs. Southern Hemisphere)
and number of prior asthma exacerbations requiring use of systemic corticosteroids in 
the previous 12 months to balance patients across study arms.  Enrollment caps for 
blood eosinophil level (Visit 1 150 vs. 150300 vs. 300 cells/L) of approximately 
35% per group during randomization will be utilized to ensure a natural distribution of 
patients in both study arms.  A permuted block randomization method will be employed.
Patients, study site personnel, contract research organization personnel, and other 
Sponsor agents (with the exception of the IxRS provider, pharmacist, and bioanalytical 
labs for excluding placebo PK samples from testing) will remain blinded to individual
treatment assignment. 


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While PK and immunogenicity (ADA) samples must be collected from patients assigned 
to the comparator arm to maintain the blinding of treatment assignment, PK and ADA 
assay results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the comparator 
arm will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Immunogenicity samples from the randomization 
visit will be analyzed for all patients.  Post-randomization immunogenicity samples from 
patients assigned to the comparator arm will not be analyzed for ADAs except by 
request.
Treatment codes should not be broken except in emergency situations.  If emergency 
unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  If the investigator wishes to know the identity of the study drug for any other 
reason, he or she should contact the Medical Monitor directly.  The investigator should 
document and provide an explanation for any premature unblinding (e.g., accidental 
unblinding, unblinding due to a serious adverse event).  Unblinding at the study site for 
any other reason will be considered a protocol deviation.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is MTPS9579A and placebo.
Methacholine is considered a non-investigational medicinal product (NIMP) for this study
as it is a bronchial challenge agent.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
MTPS9579A and Placebo
MTPS9579A or placebo will be supplied by the Sponsor as a sterile liquid in 6-cc glass 
vials for injection.  When diluted for IV administration, MTPS9579A and placebo are 
indistinguishable.  For information on the formulation and handling of MTPS9579A or 
placebo, see the pharmacy manual.


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4.3.1.2
Other Protocol-Mandated Asthma Medications
All patients must be on a stable asthma treatment regimen consisting of ICS therapy 
plus at least one additional controller medication (see Section 4.4.1 for details).  Refer to 
the local prescribing information for the formulation, packaging, and handling of these 
medications.  Patients may not be on systemic (oral, IV, or IM) corticosteroids, biologic 
agents, or experimental therapeutics for the treatment of asthma (see Section 4.4.3 for 
details).
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along 
with any associated adverse events, should be reported as described in 
Section 5.3.5.12.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.2.
The MTPS9579A/placebo dose for IV administration will be prepared by diluting study 
drug/placebo with saline.  Details regarding preparation instructions are provided in the 
pharmacy manual.  For patients who experience mild infusion-related signs or symptoms 
(Grade 2), the infusion time may be modified.  For patients with Grade 3 or higher 
infusion-related signs or symptoms requiring treatment, the infusion should be 
discontinued and the Sponsor should be notified immediately.  Patients should not be 
medicated or premedicated in order to tolerate IV administration of study drug.  Any 
changes in the rate of infusion or disruptions of infusion should be carefully documented.  
Infusions of MTPS9579A/placebo should be administered in a monitored setting where 
there is immediate access to trained personnel and adequate equipment/medicine to 
manage potentially serious reactions.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local regulations.  The study site will acknowledge receipt of IMPs supplied 
by the Sponsor using the IxRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 


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the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to MTPS9579A
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide the Genentech IMP (MTPS9579A) or any other study treatments to 
patients who have completed the study.  The Sponsor may evaluate whether to continue 
providing MTPS9579A in accordance with the Roche Global Policy on Continued Access 
to Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to screening 
(for medications not intended for the treatment of asthma) or 3 months prior to screening 
(for medications intended for the treatment of asthma) to the study 
completion/discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Asthma Therapy 
All patients will continue on a stable asthma treatment regimen, as outlined below:

Daily ICS therapy plus at least one additional controller medication (LABA, LAMA, 
LTM/LTRA) for 3 months prior to screening, with no changes within 4 weeks prior 
to screening or during the screening period and no anticipated changes in controller 
dosing regimens throughout the study
For patients receiving a total daily ICS dose of 500 g fluticasone propionate 
or equivalent, one of their additional controller medications must be LABA.
For patients receiving a total daily ICS dose of 500 g fluticasone propionate 
or equivalent, they must receive one or more of the following additional 
controller medications:  LABA, LTM/LTRA, LAMA, or long-acting theophylline 
preparations.
Any changes to the formulation or dose of ICS or any additional controller medications 
should be avoided, with the exception of the theophylline dose, which may be adjusted 
as appropriate on the basis of serum theophylline levels.  If changes to the ICS brand or 
formulation are unavoidable, the patient may be switched to another ICS brand or 
formulation at a dose equivalent to the ICS dose that the patient was receiving at study 
entry (see the study manual for examples of ICS dose equivalence).  All changes to a 
patient’s controller medications should be documented on the eCRF.


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In order to maintain stable controller medication doses, patients may not use an 
ICS/LABA combination inhaler (i.e., single maintenance and reliever therapy) as rescue 
therapy.  (Note:  This only pertains to rescue use; ICS/LABA as a stable controller 
medication is permitted.)
Restrictions on the timing of administration of bronchodilators are described in 
Section 4.5.7.
4.4.1.1
Short-Acting Rescue Therapy
It is expected that the majority of patients will be using short-acting -agonist (SABA) or 
short-acting muscarinic antagonist (SAMA) therapy for symptoms of uncontrolled asthma 
per existing treatment guidelines.  Combination SABA or SAMA inhalers (e.g., 
albuterol/ipratropium) are also permitted.  Short-acting rescue therapy must be 
administered via the patient’s prescribed inhaler or nebulizer.  Any short-acting therapy 
that is prescribed as asthma rescue medication over the course of the study or 
administered during hospitalization, an emergency department or urgent care visit, or 
urgent unscheduled office visit should be documented on the appropriate eCRF.
Restrictions on the timing of administration of SABA or SAMA therapy relative to PEFR 
and spirometry measurements are described in Section 4.4.4.
4.4.1.2
Systemic Corticosteroid Use
Patients who require any systemic corticosteroids within 4 weeks (oral or IV) or 
12 weeks (IM) prior to screening or during the screening or run-in periods will not be 
eligible for the trial (see Section 4.1.2). 
The use of systemic corticosteroids is permitted for acute asthma management after 
randomization.  Corticosteroids used for treatment of asthma (e.g., an acute 
exacerbation event as defined in Section 4.1.1.1) should be documented on the 
appropriate eCRF.  Systemic corticosteroids should not be used other than for asthma 
exacerbations, but in the event that they are used to treat other medical conditions, this 
should be documented on the Concomitant Medications eCRF.
4.4.2
Cautionary Therapy
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of asthma may be 
used during the study at the discretion of the investigator.
4.4.3
Asthma Therapy and Concomitant Restrictions
Asthma therapy and concomitant therapy restrictions are summarized in Table 1.


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Table 1
Asthma Therapy and Concomitant Therapy Restrictions
Medication
Restrictions a
Asthma Therapies
ICS therapy 
(100 g of fluticasone propionate or 
equivalent)
On a stable regimen for 3 months prior to screening, 
with no changes within 4 weeks prior to screening, 
during the screening period, or during the treatment 
period
If total daily ICS dose of 500 g fluticasone propionate 
or equivalent:

One of the additional controller medications must 
be LABA.
If total daily ICS dose of 500 g fluticasone propionate 
or equivalent:

Must receive one or more of:  LABA, LTM/LTRA, 
LAMA, or long-acting theophylline preparations
LABA therapy
LTM/LTRA therapy
LAMA therapy
On a stable regimen for 3 months prior to screening, 
with no changes within 4 weeks prior to screening, 
during the screening period, or during the treatment 
period
Allergen immunotherapy
No changes in dose or initiation of therapy within 
3 months prior to screening, during the screening  
period, or during the treatment period
Maintenance oral corticosteroids 
(daily or every other day)
Prohibited within 3 months prior to screening and during 
the screening period
Systemic corticosteroids 
(oral, IV, or IM)
Prohibited within 4 weeks (oral or IV) or 12 weeks (IM) 
prior to screening and during the screening period
Prohibited for treatment of any condition other than 
asthma exacerbations or life-threatening conditions 
(e.g., spinal cord compression, cerebral edema) during 
the study period
Bronchial thermoplasty
Prohibited within 24 months prior to screening, during 
the screening period, or during the treatment period
Maintenance intermittent positive 
pressure ventilation 
Prohibited within 2 weeks prior to screening, during the 
screening period, or during the treatment period
Maintenance bilevel positive airway 
pressure therapy
Mast cell stabilizers (e.g., chromolyn)
Licensed biologic agents 
(e.g., omalizumab, mepolizumab,
reslizumab, dupilumab)
Prohibited within 3 months or 5 drug half-lives prior to 
screening (whichever is longer), during the screening 
period, or during the treatment period
Homeopathic medications, herbal 
medications, acupuncture, or hypnosis 
Prohibited within 2 weeks prior to screening, during the 
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If the patient has not complied with the above restrictions prior to spirometry 
measurements, their visit should be rescheduled (see Section 4.5.7), with the exception 
of an unscheduled visit.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medications, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking/vaping
history, and use of alcohol and drugs of abuse, will be recorded at screening.  In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient 7 days 
prior to screening (for medications not intended for the treatment of asthma) or 3 months 
prior to screening (for medications intended for the treatment of asthma) will be 
recorded.  At the time of each follow-up limited physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
is recorded because of the potential contribution of this variable to tryptase genetics, as 
well as differences in observed pharmacokinetics, pharmacodynamics, toxicity, and/or 
response to treatment.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 


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neurologic systems.  Any abnormality identified at during the screening period should be 
recorded on the General Medical History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations and examination for infusion-related 
reactions should be performed at specified visits during the placebo-controlled period 
and as clinically indicated.  Changes from baseline abnormalities should be recorded in 
patient notes.  New or worsened clinically significant abnormalities should be recorded 
as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position (resting for at least 
5 minutes), and temperature.  Record abnormalities observed at baseline on the General 
Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
4.5.5
Nasosorption
Nasosorption is a minimally invasive technique that samples the nasal mucosal lining 
fluid using the NasosorptionFX i device (Hunt Developments), which has been used 
in humans.  The aseptic device is inserted into the nostril with the absorbent strip held 
flat against the surface of the inferior turbinate for 60 seconds as described in the study 
pulmonary function testing (PFT) manual. 
4.5.6
Fractional Exhaled Nitric Oxide
FeNO is a volatile marker of airway inflammation that decreases with ICS treatment.  
Standard nitric oxide machines (Circassia NIOXVERO Nitric Oxide Monitor) will be 
provided to the site and should be used for all study-related FeNO measurements that 
will be performed in accordance with ATS published guidelines and described in the 
study PFT manual.  Patients will be asked to refrain from nitrate-rich foods (such as 
processed meats [bacon, lunchmeat, hot dogs, sausage], spinach, green beans, 
broccoli, and cauliflower) for at least 8 hours prior to the study visit and to avoid food or 
drink for at least 1 hour prior to completing FeNO measurements.  Patients must 
complete at least three (and up to six) separate measurements to obtain at least two 
nitric oxide plateau values that agree within 10% of each other according to ATS 
guidelines (training and guidance to be provided separately) (ATS 2005; Dweik et al. 
2011). 
4.5.7
Spirometry
Spirometry, including the procedure for bronchodilator testing, will be conducted as per 
the study PFT manual, which is based on the ATS/ERS Consensus Statement 
"Standardisation of Spirometry" (Miller et al. 2005).  The manual will include information 
on equipment, procedures, patient instructions, and precautions. Standardized ATS- and 
ERS-compliant spirometric equipment (6600 VITALOGRAPH COMPACT), including 


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software, will be dispensed to all sites.  Training on equipment use, system calibration, 
and data storage and transfer will be provided.
Spirometric assessments will include FEV1, FVC, percentage of predicted values for 
FEV1 and FVC, FEV1 to FVC ratio, and average forced expiratory flow during the middle 
portion of the expiration (FEF2575).  The percentage of predicted values for FEV1 and 
FVC will be derived from the third National and Nutrition Examinations Survey 
(Hankinson et al. 1999).  Each test procedure requires that three valid spirometry 
maneuvers be performed within 1 hour.  For safety reasons, consideration should be 
given to omitting spirometry if a patient is having an acute asthma exacerbation event at 
the time of the scheduled study visit.  The acceptability of the data, including graphic 
representations of the maneuvers, will be determined by blinded over-readers.  
Calculation for the reproducibility of the acceptable maneuvers will be programmed.
Pre-bronchodilator spirometry evaluations should be performed before use of 
bronchodilators.  Asthma therapies that may affect spirometry must be withheld until pre-
bronchodilator spirometry measurements are completed.  Patients must be made aware 
that bronchodilator use is prohibited within a specified window prior to each clinic visit, 
with the exception of an unscheduled visit, as detailed in Section 4.4.4.  With the 
exception of an unscheduled visit, a patient’s pre-bronchodilator spirometry testing must 
thus be rescheduled if the patient arrives for a scheduled study visit having used a 
bronchodilator within this restricted time window.  To accommodate the rescheduled 
visit, the usual visit window specified in the schedule of activities (see Appendix 1) may 
be extended to 4 days for Week 2, 5 days for Week 3, and 6 days for all other visits.
Post-bronchodilator spirometry will be performed at screening.  During this assessment, 
up to 8 puffs of SABA or nebulized equivalent (e.g., 2 treatments with 2.5 mg 
albuterol/salbutamol) will be administered in a step-wise fashion per ATS/ERS 
guidelines (Miller et al. 2005).
4.5.8
Assessments Completed by the Patient at Home
At the initial screening visit, patients will receive an eDiary and a peak flow meter to 
measure PEFR.  Patients will be instructed in eDiary use and asked to use the eDiary 
twice per day (morning/evening) to record asthma-related symptoms, PEFR, and use of 
short-acting rescue therapy.  The eDiary will remind patients twice daily to complete their 
entries and will provide a time window during which the entry must be completed at 
approximately the same time each day.  Patients will use the eDiary during screening 
and through Week 50.  
Compliance with the required use of the eDiary and PEFR measurements (see 
Section 4.1.1.1) must be demonstrated on 5 of 7 days during each of 2 consecutive 
weeks during the screening period and also during the 2 week run-in period.  eDiary 
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will result in screen failure.  eDiary compliance less than 70% (fewer than 5 out of 7 
days/week) during the run-in period will result in study discontinuation. Site staff will 
review daily diary compliance at each subsequent visit and provide refresher training if 
compliance is consistently less than 70% between study visits.
4.5.8.1
Daily Diary Symptom-Related Asthma Assessments
The daily diary (see Appendix 4 and Appendix 5) comprises: 

Daytime/nighttime asthma symptoms 

Nighttime awakenings 

Number of doses of short-acting rescue therapy 
4.5.8.2
Peak Expiratory Flow Rate
PEFR measurements should consist of three good efforts.  Patients should complete 
their PEFR measure prior to taking their daily LABA and LAMA asthma controller 
medication as prescribed.  Patients will be given instructions on how to measure PEFR 
and record information in the eDiary.
On the days of study visits, if the patient has not performed the morning PEFR 
measurement before arrival at the clinic, the PEFR should be measured at the clinic.
4.5.9
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study’s central laboratory for 
analysis or analyzed at point of care, except where noted for pregnancy tests:

Pregnancy tests
All women of childbearing potential will have serum pregnancy tests at central 
lab at screening.  Urine pregnancy tests will be performed at sites’ local lab or 
clinic prior to each administration of study drug, and at other specified visits 
after treatment discontinuation.  Serum pregnancy tests will be confirmed at 
central labs and performed at subsequent visits if a urine pregnancy test is 
positive.  Study drug will not be administered if a patient has a positive 
pregnancy test. 

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  sodium, potassium, chloride, bicarbonate or 
total carbon dioxide (if considered standard of care for the region), glucose, BUN or 
urea, creatinine, calcium, magnesium, phosphate, total protein, albumin, total and 
direct bilirubin, ALP, ALT, AST, urate, LDH, creatine kinase, and HbA1c

HIV serology:  HIV-1/2 antibody

HBV serology:  HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb 
test is positive) HBV DNA


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If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection.

TB: QFT-G test or PPD test

Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, bilirubin, 
nitrite, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria).  If urinalysis is abnormal, reflex testing for culture and 
antibiotic sensitivity should be performed per local standard of care, if clinically 
indicated.

Urine drug screen, including, but not limited to, amphetamines, barbiturates, 
benzodiazepines, cocaine, cotinine, marijuana/cannabinoids (tetrahydrocannabinol), 
methadone, methamphetamines, methylenedioxymethamphetamine, opiates, and 
phencyclidine
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Serum samples for PK analysis

Serum samples for immunogenicity analysis

Serum, blood, urine, and nasal mucosal lining fluid samples for exploratory research 
on biomarkers
Exploratory biomarker research may include, but will not be limited to, active tryptase, 
total tryptase, urea, and inflammatory lipids. Research may involve extraction of DNA 
and genomic profiling through use of single nucleotide polymorphism analyses and next-
generation sequencing (NGS) of a comprehensive panel of genes.  Genomic research 
will be aimed at exploring inherited characteristics.  NGS methods may include whole 
genome sequencing (WGS), but only at participating sites (see Section 4.5.13). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.15), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK or immunogenicity analysis may be needed for
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.


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
Serum, urine, blood, and nasal mucosal lining fluid samples collected for biomarker 
research will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.10
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
ECGs should not be obtained within 3 hours after any meal.  Circumstances that may 
induce changes in heart rate, including environmental distractions (e.g., television, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 
recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at the study sites.  The following 
should be recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR 
duration, uncorrected QT interval, and QTcF based on the machine readings of the 
individual ECG tracings.  Any morphologic waveform changes or other ECG 
abnormalities must be documented on the eCRF.  If considered appropriate by the 
Sponsor, ECGs may be analyzed retrospectively at a central laboratory.
If at a particular postdose timepoint the QTcF is 500 ms and 60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next 5 minutes, and 
ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  


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The Medical Monitor should be notified.  Standard-of-care treatment may be instituted 
per the discretion of the investigator.  If a PK sample is not scheduled for that timepoint, 
an unscheduled PK sample should be obtained.  A decision on study drug 
discontinuation should be made, as described in Section 5.1.2.3.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia).
4.5.11
Chest X-Rays
Patients with a positive PPD test (without a history of BCG vaccination) or a QFT-G that 
is positive or indeterminate will require a chest X-ray to review for evidence of active TB, 
including posteroanterior and lateral views, unless a chest X-ray has been performed 
within 3 months prior to screening and the report is available for review.  A chest 
computed tomography scan may be substituted for a chest X-ray.  Chest X-rays should 
only be performed if patients first meet all other study eligibility criteria.
All imaging should be read by a radiologist or per local requirements.
4.5.12
Asthma Exacerbations
At each study visit, the investigator will ask directed questions to assess whether the 
patient experienced any asthma exacerbations as defined in Section 2.1.1 since the last 
study visit.
Given that asthma exacerbations comprise part of the primary endpoint in this study, a 
dedicated eCRF will be used to record information regarding asthma exacerbation 
events.  An asthma exacerbation must also be reported as an adverse event (or serious 
adverse event, as applicable) (refer to Section 5.3.5.10 for more details).  Sites should 
record all medications used for treatment of the asthma exacerbation in the appropriate 
eCRF. 
Patients who experience symptoms consistent with an asthma exacerbation should be 
asked to come to the clinic for an unscheduled visit if possible.  Additional evaluations 
will be performed as outlined in the schedule of activities (see Appendix 1).
4.5.13
Blood Samples for Whole Genome Sequencing (Patients at 
Participating Sites)
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
to identify variants that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Research will be aimed at exploring inherited characteristics.  The samples 
may be sent to one or more laboratories for analysis.


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Collection and submission of blood samples for WGS is contingent upon the review and 
approval of the exploratory research by each site's Institutional Review Board or Ethics 
Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for WGS, this section of the protocol (Section 4.5.13) will not be 
applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
Refer to Section 4.5.9 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses.
4.5.14
Optional Methacholine Challenge Test
Consenting patients who meet additional inclusion criteria (Section 4.1.1.3) will undergo 
an optional methacholine challenge test, which should be performed before study drug 
dosing and within the visit windows for randomization and the Week 30 visit.  
Methacholine challenge will be performed using standard techniques (Coates et al. 
2017) and as described in the study PFT manual.  
The Informed Consent Form will contain a separate section that addresses this optional 
test.  A separate, specific signature will be required to document a patient's agreement 
to undergo optional testing.  The investigator should document whether the patient has 
given consent to participate and (if applicable) the date(s) of consent, by completing the 
Optional Methacholine Challenge Test Informed Consent eCRF.
4.5.15
Optional Samples for Research Biosample Repository
4.5.15.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 


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solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.15.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.15) 
will not be applicable at that site.
4.5.15.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to MTPS9579A, diseases, or 
drug safety:

Leftover blood, serum, nasal mucosal lining fluid, and urine samples and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides) 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS or other genomic analysis methods. Genomics is increasingly 
informing researcher's understanding of disease pathobiology.  WGS provides a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 


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dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.15.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.15.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.


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In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.15.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.15.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Any Grade 4 adverse event that the investigator or Sponsor determines to be 
related to study treatment.  This excludes asthma exacerbations, unless they meet 
one of the other criteria for study treatment discontinuation.


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
Investigator or Sponsor determination that treatment discontinuation is in the best
interest of the patient

Pregnancy

Suspicion of hypersensitivity or anaphylactic reaction to study drug (i.e., generalized
urticaria or angioedema [WHO Grade 3 allergic reaction] or anaphylaxis [Grade 4
allergic reaction] related to study drug, or Grade 3 or 4 infusion related reaction)
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced and should continue follow-up for all other study procedures and 
measurements through the end of the study (Week 58).  
4.6.2
Patient Discontinuation from the Study
Patients who discontinue the study prematurely will return to the clinic for a safety 
follow-up visit at Week 54 or for the early termination visit.
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced. 
Patients who enter the run-in period but fail to meet the additional eligibility criteria for 
the double-blind treatment period (see Section 4.1.1.2) should be discontinued from the 
study and prohibited from re-screening.  In addition, these patients should be informed 
that the first dose given at the start of run-in was a placebo and, therefore, they are not 
required to return for follow-up visits.  Patients who fail run-in will be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a
potential health hazard to patients


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
Any emerging aggregate safety signals from serious or Grade 3 or higher adverse 
events evaluated by the unblinded IMC (as specified in Section 3.1.3) that indicates 
a potential health hazard

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
MTPS9579A is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with MTPS9579A in studies with 
healthy volunteers.  The anticipated important safety risks for MTPS9579A are outlined 
below.  Refer to the MTPS9579A Investigator's Brochure for a complete summary of 
safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  Ongoing review of 
safety will be performed by the Sponsor.  In addition, guidelines for managing adverse 
events, including criteria for treatment interruption or discontinuation, are provided 
below.
5.1.1
Risks Associated with MTPS9579A
MTPS9579A is a monoclonal antibody, and like all protein-based therapeutics, it carries 
a potential for immunogenicity leading to hypersensitivity and injection-site or 
infusion-related reactions.  Tryptase is not thought to play a role in homeostatic function, 
and at this time, neither nonclinical nor clinical data indicate any important potential risks 
based on its mechanism of action.  Clinical and nonclinical data do not suggest 
additional potential risks.  Inclusion and exclusion criteria for this study are designed 
such that comorbidities are minimized and would not place patients at additive risk.


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5.1.1.1
Immunogenicity
The development of ADAs is a potential risk for all protein therapeutics (such as 
monoclonal antibodies).  Administration of MTPS9579A, a monoclonal antibody against 
tryptase, may lead to the development of anti-MTPS9579A antibodies.  Patients who 
develop ADAs may experience adverse events or reduced efficacy.
Serum samples will be collected at protocol-defined intervals (see Appendix 1) to 
monitor for the development of ADAs.  Patients who test positive for antibodies against 
MTPS9579A and have clinical sequelae that are considered related to ADAs may be 
asked to return for additional follow-up testing.
5.1.1.2
Hypersensitivity/Hypersensitivity-Like Reactions and 
Anaphylaxis/Anaphylactoid Reactions
Hypersensitivity reactions and anaphylaxis have been described with SC or IV 
administration of monoclonal antibodies (Corominas et al. 2014).  Signs and symptoms 
may include acute onset (minutes to several hours) of one or more of the following:  
respiratory compromise, reduced blood pressure, skin-mucosal involvement, or 
gastrointestinal symptoms (Sampson et al. 2006).  See Appendix 6 for anaphylaxis 
precautions and management.
No hypersensitivity/hypersensitivity-like reactions or anaphylaxis/anaphylactoid reactions 
associated with MTPS9579A were observed following a single IV dose or repeat IV and 
SC doses in cynomolgus monkeys.  The potential for hypersensitivity to MTPS9579A in 
humans is unknown.  However, to date, there have been no reports of anaphylaxis or 
systemic hypersensitivity among subjects enrolled in the Phase I clinical trial of 
MTPS9579A in healthy volunteers, even among those who developed ADAs.
Systemic allergic reactions have also not been observed in the Phase I clinical study in 
healthy volunteers.  However, as with any large-molecule therapeutic, administration of 
MTPS9579A may result in systemic reactions.  Systemic reactions to large-molecule 
therapeutics can be IgE mediated; however, they may also be non-IgE mediated or due 
to cytokine release. Systemic reactions are generally characterized by signs and 
symptoms that include skin rash, urticaria, pruritus, local or diffuse erythema, 
angioedema, fever, chills, cough, dyspnea, wheezing, bronchospasm, nausea, vomiting, 
diaphoresis, chest pain, tachycardia or bradycardia, and/or hypotension, which can be 
severe or life threatening.  Effects typically occur during drug administration, or within 
several hours of administration, but they may be delayed.
Patients with a history of anaphylaxis, hypersensitivities, or drug allergies to antibody 
therapeutics will be excluded from studies with MTPS9579A.
Investigators and healthcare professionals administering MTPS9579A should be trained 
to recognize and manage the signs and symptoms of a potential anaphylactic, 


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anaphylactoid, or hypersensitivity reaction and should be familiar with Sampson’s 
criteria for defining anaphylaxis (Sampson et al. 2006; see Appendix 6).
Investigators and healthcare professionals should also be trained to accurately and 
appropriately report these events immediately to the Sponsor as adverse events of 
special interest, and as serious adverse events if appropriate (see Section 5.2). 
Healthcare professionals should also instruct patients on how to recognize the 
symptoms of any anaphylactic, anaphylactoid, or hypersensitivity reaction and to contact 
a healthcare provider or seek emergency care in case of any such symptoms. Patients 
will need to be clinically stable prior to each dose of study drug as assessed by clinical 
evaluations, including vital signs and spirometry/PEF measurements.
5.1.1.3
Infusion-Related Reactions
In patients who receive study drug intravenously, infusion-related reactions may occur.  
These may be acute—often overlapping in symptoms with a hypersensitivity or 
anaphylactic reaction.  Should such an acute reaction take place, the patient should be 
managed following the scheme as for anaphylaxis (see Appendix 6).  Infusion-related 
reactions may also be delayed, occurring hours to days (up to 14 days) after 
administration.  These delayed symptoms are frequently similar to those of serum 
sickness:  rash, vasculitis, erythema multiforme, Stevens-Johnson syndrome, and toxic 
epidermal necrolysis (Corominas et al. 2014).  If a delayed infusion-related reaction is 
suspected, the patient should discontinue study drug, and appropriate clinical 
management should be applied.
In the Phase I clinical study in healthy volunteers, no subjects have had any 
infusion-related reactions.
5.1.1.4
Injection-Site Reactions
Injection-site reactions have been described with SC administration of monoclonal 
antibodies (Corominas et al. 2014).  If SC exposure occurs at the IV infusion site, signs 
and symptoms may include pain, itching, erythema, and swelling at the injection site.  
The reaction may be immediate, although it usually appears within 2448 hours, with 
variability of incidence relating primarily to the specific drug administered.  Injection-site 
reactions may be self-limited but may require local and/or systemic therapy for severe 
reactions.
No clinically significant injection-site reactions associated with MTPS9579A were 
observed following single or repeat doses in cynomolgus monkeys.  
In Phase I clinical trials of MTPS9579A in healthy volunteers, approximately 29% of 
participants developed injection-site erythema, and approximately 11% of subjects 
developed injection-site or administration-site pallor.  These reactions were mild (WHO 
Grade 1) and self-limited, typically appearing 1 hour after administration and resolving 
within 2 hours.


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5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Treatment Interruption
Reduction in dosing for adverse events is not permitted. Patients who experience 
certain adverse events considered to be related to study drug should be discontinued 
from treatment as described in Section 4.6.1. 
Study treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug. If study treatment has been withheld for two or 
more consecutive dosing visits because of toxicity, the patient should be discontinued 
from study treatment. However, if the adverse event(s) that led to withholding dosing 
shows clear evidence of improvement, treatment may be resumed following discussion 
with and approval by the Medical Monitor. Study treatment may be suspended for 
reasons other than toxicity (e.g., surgical procedures), but must be approved by the 
Medical Monitor. The investigator and the Medical Monitor will determine an acceptable 
length of time for the treatment interruption.
5.1.2.2
Management Guidelines for Hepatotoxicity
Table 2 provides specific guidelines for withholding or discontinuing study drug for 
patients who experience hepatotoxicity. 


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Table 2
Guidelines for Treatment Interruption or Discontinuation for 
Patients Who Experience Hepatotoxicity
Event
Actions to Be Taken
Hepatotoxicity
ALT or AST increase that meets Hy’s Law 
criteria: ALT or AST 3 ULN in 
combination with TBILI 2 ULN or clinical 
jaundice
Discontinue MTPS9579A
If criteria for Hy’s Law are not met: 
ALT or AST increase that meets at least one 
of the following criteria:

> 8 ULN

> 5 ULN for 2 weeks

3 ULN with clinical signs or symptoms 
that are consistent with hepatitis (e.g., 
right upper quadrant pain or tenderness, 
fever, nausea, vomiting, jaundice)
Withhold MTPS9579A. Treatment may be 
resumed if an alternative cause is identified and 
laboratory values have resolved to those at the 
randomization visit.  If signs or symptoms recur, 
permanently discontinue MTPS9579A.
If criteria for Hy’s Law are not met: 
TBILI 3 ULN
or
Withhold MTPS9579A. Treatment may be 
resumed if an alternative cause is identified and 
laboratory values have resolved to those at the 
randomization visit.  If signs or symptoms recur, 
permanently discontinue MTPS9579A.
Alkaline phosphatase 3 ULN
TBILItotal bilirubin; ULNupper limit of normal.
5.1.2.3
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained absolute (at least two ECG measurements 30 minutes apart) QTcF that 
is 500 ms or 60 ms longer than the baseline value

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 


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of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  
In such a situation, saving all available ECG data is highly suggested. 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended to help 
in the management of such patients.  The Medical Monitor should be notified as soon as 
possible.  In more complicated or severe occurrences, hospitalization should be 
considered.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing protocol-
specified safety laboratory assessments, measuring protocol-specified vital signs, and 
conducting other protocol-specified tests that are deemed critical to the safety evaluation 
of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can, 
therefore, be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., methacholine challenge)


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5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to WHO 
Toxicity Grading Scale; see Section 5.3.3); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 


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considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Grade 3 allergic reaction within 24 hours of infusion or suspected to be due to 
study drug  
Grade 3 allergic reactions include generalized urticaria and angioedema 
(Grade 3) and anaphylaxis (Grade 4).
5.2.4
Selected Adverse Events
Additional data will be collected for the following selected adverse events:

Adverse event information related to the predose optional methacholine challenge 
test should only be collected if it is a serious adverse event (see Section 5.3.1).

Adverse event information related to the optional Week 30 methacholine challenge 
test should be collected and the relatedness to the procedure should be captured in 
the appropriate eCRF.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 12 weeks after the 
final dose of study drug or until discontinuation from the study, whichever occurs later.
However, for patients who receive placebo during run-in but fail to be randomized, 
adverse events will be reported only until 6 weeks after the placebo dose. After this 
period, the Sponsor should be notified if the investigator becomes aware of any serious 


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adverse event that is believed to be related to prior study drug treatment (see 
Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The WHO Toxicity Grading Scale (see Appendix 7) will be used for assessing adverse 
event severity.  Table 3 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO Toxicity Grading Scale.
Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention or 
therapy required
2
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible
4
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

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
Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related or Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related or anaphylactic reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related or injection reactions (see 
Section 5.3.5.1), a diagnosis (if known) should be recorded on the Adverse Event eCRF 
rather than individual signs and symptoms (e.g., record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or 


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syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5upper limit of normal [ULN] associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.


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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed solely to exacerbation of asthma.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to asthma exacerbation, "asthma exacerbation" should be 
recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Worsening of Asthma
Medical occurrences or symptoms of deterioration that are anticipated as part of asthma 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study (e.g., an asthma exacerbation).  When recording an unanticipated worsening 
of asthma on the Adverse Event eCRF, it is important to convey the concept that the 
condition has changed by including applicable descriptors (e.g., "asthma exacerbation").
Asthma exacerbation is defined as an acute worsening of asthma that requires a burst of 
systemic corticosteroids (refer to Section 2.1.1).  
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2) except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease (for example, progressive osteoarthritis 
necessitating a hip replacement surgery).
The patient has not experienced an adverse event.


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours

Hospitalization that was pursued for convenience to efficiently carry out multiple 
outpatient tests
5.3.5.12
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
MTPS9579A, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with MTPS9579A, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event).  Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from patient-reported outcome (PRO) data by 
the Sponsor, and safety analyses will not be performed using PRO data.  Sites are not 
expected to review the PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information
Genentech Medical Monitor contact information:
Medical Monitors and Telephone Nos:
, M.D., Ph.D. (Primary)
Office:  
 (United States) 
Mobile:  
 (United States) 
, M.D. (Secondary)
Office:  
 (United States)
Mobile:  
(United States)
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug (including 
single-blinded placebo during the run-in), only serious adverse events caused by a 
protocol-mandated intervention should be reported.  The paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 84 days after the final dose of study drug or until end of 
study (Week 58) for patients who discontinue study drug but remain on study.  For 
patients who receive placebo during run-in but fail to be randomized, serious adverse 
events and adverse events of special interest will be reported until 6 weeks after the 
placebo dose.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 


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EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur following completion of the 
adverse event reporting period described above are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 60 days after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
60 days after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the
treating physician and/or obstetrician.


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5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.


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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
84 days after the final dose of study drug or end of study (Week 58) for patients who 
discontinue study drug but remain on study, or 6 weeks following the placebo dose for 
patients who failed to be randomized), if the event is believed to be related to prior study 
drug treatment.  These events should be reported through use of the Adverse Event 
eCRF.  However, if the EDC system is not available, the investigator should report these 
events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

MTPS9579A Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An IMC will monitor the incidence of the above-listed anticipated events during the study 
(see Section 3.1.3).
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary and secondary efficacy analyses will be based on a modified intent-to-treat 
(mITT) approach.  All patients randomized who received at least one dose of study drug 
will be included in the mITT analysis set and be included in the analysis, with patients 
grouped according to the treatment assigned at randomization.


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All safety analyses will include all randomized patients who received any study drug.  
For these analyses, patients will be grouped according to the treatment actually 
received.
An interim efficacy analysis is planned to be performed after approximately 51 patients 
have experienced a CompEx event in the 48-week, double-blind treatment period.  For 
the interim analysis, the treatment assignments will be unblinded to relevant Sponsor 
study team members performing the analyses.  The other parties who are involved in the 
conduct of the study (e.g., patients, site monitors, investigators) will remain blinded to 
patient-specific treatment assignments until the final database lock after the completion 
of the study. 
The final analysis of data will be performed when all patients have either completed the 
study completion/early termination visit or discontinued early from the study.  In addition, 
all data collected from the study will be cleaned, verified, and locked in a database. 
All primary and secondary hypotheses tests will be two-sided with a type I error rate of 
0.2.  To aid the interpretation and understand the clinically significant differences from 
the formal hypothesis testing, two-sided 95% confidence intervals will be provided.  
There will be no adjustment made for any multiple comparisons.  In addition, there will 
be no type I error control methods triggered as a result of the interim analysis.   
Detailed specifications of all statistical methods (including scoring of PRO instruments 
and missing data handling) will be provided in the Data Analysis Plan (DAP).
6.1
DETERMINATION OF SAMPLE SIZE
The primary goal of this trial is estimation rather than hypothesis testing.  This is largely 
due to the uncharacterized distribution of CompEx in the placebo arm.  The interim 
analysis based upon 51 events will yield reasonable precision for estimating the true 
underlying hazard ratio.  
 
 
 
 
 
 
  
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue (early discontinuation of treatment or 
early termination from the study), or complete the study will be summarized.  Reasons 
for early discontinuation of treatment or premature study withdrawal will be listed and 
summarized by treatment group.  Enrollment and major protocol deviations will be listed 
and evaluated for their potential effects on the interpretation of study results.  All 
summaries will be presented according to randomized treatment assignment.


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6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Baseline demographics, disease characteristics, and exposure to study drug will be 
summarized overall and by treatment group using descriptive statistics.  For categorical 
endpoints, the descriptive statistics will include counts and proportions.  For continuous 
endpoints, the descriptive statistics will include the number of observations, mean, 
standard deviation, median, minimum, and maximum.
6.4
EFFICACY ANALYSES
Efficacy analyses will be conducted on an mITT population, consisting of all randomized 
patients who received at least one dose of study drug during the 48-week double-blind 
treatment period, with patients grouped according to the treatment assigned at 
randomization. 
Unless otherwise noted, analyses of efficacy outcome measures will be adjusted by
blood eosinophil level (Visit 1 150 cells/L, 150300 cells/L, 300 cells/L) and 
geographic region (United States/Western Europe, Eastern Europe, Southern 
Hemisphere).
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is time to first CompEx event, defined as time from 
randomization to first asthma exacerbation or diary worsening during the 48-week 
double-blind treatment period.  Asthma exacerbations and diary worsening are defined 
as follows: 

Asthma exacerbations are assessed by the investigator and defined as new or 
increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/ 
or nighttime awakenings due to these symptoms) that result in one or both of the 
following:
–
Hospitalization or an emergency department or urgent care visit requiring 
administration of systemic corticosteroid treatment 
–
Treatment with systemic (IV, IM, or oral) corticosteroids for 3 days or a 
long-acting depot corticosteroid preparation with a therapeutic effectiveness of 
3 days

Diary worsening is based on the occurrence of prespecified changes (deteriorations) 
in the following six parameters: morning PEFR, evening PEFR, morning symptom 
score, evening symptom score, morning short-acting rescue therapy use, and 
evening short-acting rescue therapy use.  Deterioration criteria, defined as either a 
change from baseline (threshold) or worsening of a certain magnitude (slope) over 
5 consecutive days, are presented for each parameter in Appendix 8.  Diary 
worsening is defined as occurrence of one or both of the following scenarios:


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–
Patient meets threshold deterioration criterion (i.e., prespecified change from 
baseline) for PEFR (morning and/or evening) and at least one other parameter 
(i.e., morning symptom score, evening symptom score, morning rescue therapy 
use, and/or evening rescue therapy use) on 2 consecutive days.
–
Patient meets threshold deterioration criterion (i.e., prespecified change from 
baseline) for one parameter on 2 consecutive days and slope deterioration 
criterion (i.e., prespecified change over 5 consecutive days calculated via 
univariate linear regression) for all six parameters.
For the purposes of determining whether the threshold deterioration criteria are met, 
baseline levels are calculated for each individual as the mean over the 10 planned 
sessions conducted prior to time of randomization for each of the diary variables.
In the event that the first diary worsening scenario is met (i.e., threshold met in two 
parameters), the diary worsening event will start on the first of the 2 consecutive days 
(defined as Event Days 0 and 1). 
In the event that the second diary worsening scenario is met (i.e., threshold in one 
parameter and slope in all six parameters), the diary worsening event will start on the 
first of the 2 consecutive days that the threshold was met (Event Days 0 and 1), and the 
slope criteria for the six parameters must be met on Day 0 and the 4 consecutive days 
prior to that day (i.e., Event Day 4 through Event Day 0).  
To qualify for the second diary worsening scenario, data from at least 3 of the 5 
consecutive days must be available for calculation of the slope for each parameter.  
Analyses will be based on observed asthma exacerbations and diary worsenings, with 
no imputation for premature discontinuation or missing diary entries.
The primary endpoint will be analyzed through use of a Cox proportional hazards 
regression model comparing MTPS9579A with placebo with respect to time to first 
CompEx event, with adjustment for baseline covariates as described in Section 6.4.  
Estimated hazard ratios and their associated 95% confidence intervals will be provided.  
Further details regarding the primary endpoint and the analysis will be described in the 
DAP.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Rate of asthma exacerbations (as defined in Section 2.1.1) during the 48-week 
double-blind treatment period

Time to first asthma exacerbation during the 48-week double-blind treatment period

Absolute and relative change from randomization in pre-bronchodilator FEV1 (liters) 
at Week 50

Absolute and relative change from randomization in FeNO at Week 50


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The secondary endpoints will be evaluated in the mITT population.  Statistical models 
will be adjusted for baseline covariates, as described in Section 6.4.  The annualized 
exacerbation rate will be estimated for each arm as the total number of protocol-defined 
asthma exacerbations observed over the treatment period divided by total patient-years
at risk.  For each individual patient, years at risk will be computed as the number of days 
from the date of randomization to the date of treatment completion or discontinuation, 
divided by 365.25 days.  Poisson regression with over-dispersion will be used in the 
analysis to assess the treatment effect on the rate of asthma exacerbations.  Analyses 
will be based on observed exacerbations, with no imputation for premature 
discontinuation.  In addition, a patient’s time at risk, as defined above, will be computed 
and used as an offset term in the model. 
Continuous endpoints will be analyzed using mixed-model repeated measures.  Time-to-
event endpoints will be analyzed using a Cox proportional hazards regression model.  
For the categorical variables, appropriate statistical methods, such as Cochran-Mantel-
Haenszel test or Fisher’s exact test, will be used.  Descriptive summaries for continuous 
endpoints will include mean, standard deviation, median, and range.  Descriptive 
summaries for categorical endpoints will include counts and proportions. 
Descriptive summaries for continuous endpoints will include mean, standard deviation, 
median, and range.  Descriptive summaries for categorical endpoints will include counts 
and proportions.  Further details will be described in the DAP.
6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

Rate of severe asthma exacerbations during the 48-week double-blind treatment 
period, defined as asthma symptoms requiring hospitalization or resulting in death 
attributed to asthma

Absolute change from randomization in pre-bronchodilator FEV1 (percentage 
predicted) at Week 50

Absolute change from randomization in patient-reported daytime asthma symptom 
severity, as measured by a daily symptom diary (as defined in primary efficacy 
objective), at Week 50

Absolute change from randomization in patient-reported nighttime asthma symptom 
severity, as measured by a daily symptom diary (as defined in primary efficacy 
objective), at Week 50

Absolute change from randomization in patient-reported number of puffs of short-
acting rescue inhaler or number of times nebulizer was used at Week 50

Absolute and relative change from randomization visit in PD20 as a measure of 
airway hyper-responsiveness at Week 30, in patients who consent to this optional 
assessment at select sites
Analysis of exploratory efficacy endpoints will be described in the DAP.


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6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug during the 48-week double-blind treatment period, with 
patients grouped according to treatment received (MTPS9579A or placebo). Safety 
analysis of run-in patients will consist of all patients who received the single-blind 
placebo dose during the run-in period, regardless of whether or not the patient is 
randomly allocated into the double-blind treatment period. For this safety analysis, only 
events that occur during the 2-week run-in period will be included and grouped together
since all patients will have received placebo.
Safety will be assessed through summaries of adverse events, laboratory test results, 
ECG parameters, physical examination findings, and vital signs.  Verbatim descriptions 
of treatment-emergent adverse events will be coded using the MedDRA thesaurus terms 
and their severity by WHO Toxicity Grading Scale (see Appendix 7), and their incidence 
will be summarized by treatment arm.  A treatment-emergent adverse event is defined 
as any new adverse event reported or worsening of an existing condition on or after the 
first dose of study drug during the 48-week double-blind treatment period.  In addition, 
separate summaries will be generated for serious adverse events, adverse events of 
special interest, deaths, pregnancies, malignancies, anaphylaxis events, adverse events 
leading to discontinuation from the study, and adverse events leading to discontinuation 
of study drug. 
Clinical laboratory data (serum chemistry, hematology evaluations, and urinalysis 
values) and vital signs will be summarized by descriptive statistics for each treatment 
group.
6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will include patients with sufficient data to enable estimation 
of key parameters (e.g., peak serum concentration and predose trough concentrations). 
Serum study drug concentrations at selected timepoints will be tabulated and 
summarized by descriptive statistics.  The extent of interpatient variability will be 
evaluated, and potential sources of variability will be assessed.  Relationships between 
exposure and PD, efficacy, and safety endpoints will be explored.
Additional PK analyses will be conducted during and/or at the end of study as 
appropriate.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.


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The numbers and proportions of ADA-positive patients and ADA-negative patients at 
randomization (baseline prevalence) and after drug administration (postbaseline 
incidence) will be summarized by treatment group.  When determining postbaseline 
incidence, patients are considered to be ADA positive if they are ADA negative or have 
missing data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Biomarkers will be assessed to determine pharmacological activity and mechanism of 
action of MTPS9579A.  Data will be summarized by absolute levels of the biomarker, as 
well as absolute and relative changes from randomization (defined as predose), for each 
treatment group.  Additional PD analyses will be conducted as appropriate.
Potential predictive biomarkers of MTPS9579A response will be assessed in primary 
and key secondary endpoints (e.g., CompEx, asthma exacerbation rate) to assess if a 
subset of patients derives enhanced clinical benefit from MTPS9579A.  Predictive 
biomarker candidates include, but are not limited to, blood eosinophils and germline 
mutations in the genes encoding tryptase (TPSAB1 and TPSB2). 
Further details related to biomarker analyses will be described in the DAP.  
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analysis
An interim analysis will take place after approximately 51 patients have experienced a 
CompEx event in this study.  The expected timing of the interim analysis will be 
approximately 60 weeks after the first patient is randomized. No formal stopping rules or 
decision criteria have been defined for the result of the interim analysis.
The interim analysis will be performed and interpreted for potential enrollment decisions 
(e.g., temporary or permanent enrollment halt, change to number of total randomized 
patients), for early study termination, or for administrative purposes (e.g., planning of 
future studies) by members of the Sponsor study team and appropriate senior 
management personnel, who will be unblinded at the treatment group level.


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Access to treatment assignment information will follow the Sponsor’s standard 
procedures.
6.9.2
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two additional interim efficacy analyses (i.e., beyond what is specified in 
Section 6.9.1).  The decision to conduct an optional interim analysis and the timing of the 
analysis will be documented in the Sponsor's trial master file prior to the conduct of the 
interim analysis.  The interim analysis will be performed and interpreted for potential 
enrollment decisions (e.g., temporary or permanent enrollment halt, change to number 
of total randomized patients), for early study termination, or for administrative 
purposes (e.g., planning of future studies) by members of the Sponsor study team and 
appropriate senior management personnel, who will be unblinded at the treatment group 
level.  Access to treatment assignment information will follow the Sponsor's standard 
procedures.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
An electronic device will be used to capture PRO data at home.  The device is designed 
for entry of data in a way that is attributable, secure, and accurate, in compliance with 
U.S. Food and Drug Administration (FDA) regulations for electronic records (21 CFR 
Part 11).  The data will be transmitted to a centralized database maintained by the 
electronic device vendor.
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial-
related monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic and paper PRO data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 


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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 


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each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 


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prospective requests to deviate from the protocol, including requests to waive protocol
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior 
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring.
Approximately 55 sites globally will participate to enroll approximately 160 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.9.  
The Sponsor will monitor and evaluate patient safety throughout the study.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 


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met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
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when used to treat asthma: an overview of Cochrane systematic reviews. Respir 
Med 2006;100:1297306.
[ATS] American Thoracic Society. ATS/ERS recommendations for standardized 
procedures for the online and offline measurement of exhaled lower respiratory 
nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 
2005;171:91230.
Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be 
achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med 
2004;170:83644.
Bloom CI, Palmer T, Feary J, et al. Exacerbation patterns in adults with asthma in 
England: a population based study. Am J Respir Crit Care Med 2018. doi: 
10.1164/rccm.201808-1516OC [Epub ahead of print].
Bradding P, Arthur G. Mast cells in asthmastate of the art. Clin Exp Allergy 
2016;46:194263.
Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth 
muscle in asthma. N Engl J Med 2002;346:1699705.
[CDC] Centers for Disease Control and Prevention. Asthma surveillance data [resource 
on the Internet]. 2014 [updated 8 September 2016; cited 10 February 2019]. 
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Choy D, Trivedi N, Dressen N, et al. Tryptase loss-of-function mutations reduce tryptase 
expression and predict asthmatic response to anti-IgE therapy Eur Respir J 
2018;52(suppl 62):OA1652.
Clark JM, Van Dyke RE, Kurth MC. Tryptase inhibition. In: Hansel TT, Barnes PJ, 
editors. New drugs for asthma, allergy, and COPD. Progress in respiratory 
research, vol. 31. Basel:Karger, 2001:1702.
Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial 
challenge testing: general considerations and performance of methacholine 
challenge tests. Eur Respir J 2017;49:1601526.
Corominas M, Gastaminza G, Lobera T. Hypersensitivity reactions to biological drugs. 
J Investig Allergol Clin Immunol 2014;24:21225.
Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: 
interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J 
Respir Crit Care Med 2011;184:60215.
Fuhlbrigge AL, Begtsson T, Peterson S, et al. A novel endpoint for exacerbations in 
asthma to accelerate clinical development: a post-hoc analysis of randomized 
controlled trials. Lancet Respir Med 2017;5:57790.


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Global Asthma Network. The Global Asthma Report [resource on the Internet]. 2018 
[cited 10 February 2019]. Available from: http://globalasthmareport.org.
[GINA] Global Initiative for Asthma. Global strategy for asthma management and 
prevention. 2018 [cited 10 February 2019]. Available from: https://ginasthma.org/wp-
content/uploads/2018/04/wms-GINA-2018-report-V1.3-002.pdf
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample 
of the general US population. Am J Respir Crit Care Med 1999;159:17987.
He S, Aslam A, Gaça MD, et al. Inhibitors of tryptase as mast cell-stabilizing agents in 
the human airways: effects of tryptase and other agonists of proteinase-activated 
receptor 2 on histamine release. J Pharmacol Exp Ther 2004;309:11926.
Holt S, Suder A, Weatherall M, et al. Dose–response relation of inhaled fluticasone 
propionate in adolescents and adults with asthma: meta-analysis. BMJ 
2001;323:2536.
Krishna MT, Chauhan A, Little L, et al. Inhibition of mast cell tryptase by inhaled APC 
366 attenuates allergen-induced late-phase airway obstruction in asthma. J Allergy 
Clin Immunol 2001;107:103945.
Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Childhood Asthma Research and 
Education (CARE) Network of the National Heart, Lung, and Blood Institute. 
Step-up therapy for children with uncontrolled asthma receiving inhaled 
corticosteroids. N Engl J Med 2010;362:97585.
Masoli M, Holt S, Weatherall M, et al. Dose-response relationship of inhaled budesonide 
in adult asthma: a meta-analysis. Eur Respir J 2004a;23:5528.
Masoli M, Holt S, Weatherall M, et al. The dose–response relationship of inhaled 
corticosteroids in asthma. Curr Allergy Asthma Rep 2004b;4:1448.
Masoli M, Weatherall M, Holt S, et al. Moderate dose inhaled corticosteroids plus 
salmeterol versus high doses of inhaled corticosteroids in symptomatic asthma. 
Thorax 2005;60:7304.
Miller MR, Hankinson J, Brusasco V, et al. ATS/ERS Task Force: standarisation of lung 
function testing. Eur Respir J 2005;26:31938. 
[NHLBI] National Heart, Lung, and Blood Institute and National Asthma Education and 
Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and 
management of asthma [resource on the Internet]. 2007 [cited 10 February 2019]. 
Available from: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.
Payne V, Kam PC. Mast cell tryptase: a review of its physiology and clinical significance. 
Anaesthesia 2004;59:695703. 
Peters SP, Ferguson G, Deniz Y, et al. Uncontrolled asthma: a review of the prevalence, 
disease burden and options for treatment. Respir Med 2006;100:113951. 


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Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary reportSecond National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117:3917.
Sears MR, Ottosson A, Radner F, et al. Long-acting β-agonists: a review of formoterol
safety data from asthma clinical trials. Eur Resp J 2009;33:2132.
Sommerhoff CP. Mast cell tryptases and airway remodeling. Am J Respir Crit Care Med 
2001;164(Suppl 2):S528.
Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term 
prevention of hospitalisation for asthma. Thorax 2002;57:8804.
Szefler SJ, Martin RJ, King TS, et al. Asthma Clinical Research Network of the National 
Heart Lung, and Blood Institute. Significant variability in response to inhaled 
corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:4108.
To T, Stanojevic S, Moores G, et al. Global asthma prevalence in adults: findings from 
the cross-sectional world health survey. BMC Public Health 2012;12:204.
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guidelines for programmatic management. 2018  [resource on the Internet]. 2018 
[cited 10 February 2019]. Available from: 
https://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/
Wong CA, Walsh LJ, Smith CJP, et al. Inhaled corticosteroid use and bone-mineral 
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Zhang M-Q, Timmerman H. Mast cell tryptase and asthma. Mediators Inflamm 
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Appendix 1
Schedule of Activities
Screeninga
Run-Inb
Rand.c
Treatment
EOTd
Safety 
Follow
-Up
Safety 
T/Ce
UVf ETg
Day
(Window) –28 to –1
1
15 
(2)
23 
(2)
44 
(3)
72 
(3)
100 
(3)
128 
(3)
156 
(3)
184 
(3)
212 
(3)
240 
(3)
268 
(3)
296 
(3)
324 
(3)
352 
(4)
380
(3)
408 
(3)
Week
4 to 0
0
2
3
6
10
14
18
22
26
30
34
38
42
46
50
54
58
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Informed consent h
x
Demographic data
x
Medical history and 
baseline conditions
x
eDiary and peak flow 
meter distribution
x
Weight
x
x
x
x
Height
x
Complete physical 
examination i
x
x
x
Limited physical 
examination j
x
x
x
x
x
x
x
x
x
x
Review eligibility criteria
x
x
x
k,u
Vital signs l
x
x m
x m
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
x
x
x
Concomitant 
medications n
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine drug screen o
x
x
x


Appendix 1: Schedule of Activities
MTPS9579A—Genentech, Inc.
99/Protocol GB41149, Version 4
Screeninga
Run-Inb
Rand.c
Treatment
EOTd
Safety 
Follow
-Up
Safety 
T/Ce
UVf ETg
Day
(Window) –28 to –1
1
15 
(2)
23 
(2)
44 
(3)
72 
(3)
100 
(3)
128 
(3)
156 
(3)
184 
(3)
212 
(3)
240 
(3)
268 
(3)
296 
(3)
324 
(3)
352 
(4)
380
(3)
408 
(3)
Week
4 to 0
0
2
3
6
10
14
18
22
26
30
34
38
42
46
50
54
58
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Hematology p
x
x q
x
x
x
x
x
x
x
x
x
x
Chemistry r
x
x
x
x
x
x
x
x
x
x
x
Urinalysis s
x
x
x
x
x
x
Pregnancy test t
x
x u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Viral serology v
x
TB test w
x
ECG  (single record)
x
x
x
x
x
x
x
x
FeNO x
x
x
x u
x
x
x
x
x
x
x
x
x
x
Pre-bronchodilator 
spirometry y
x
x
x u
x
x
x
x
x
x
x
x
x
x
Post-bronchodilator 
spirometry (reversibility)
x
Optional methacholine 
challenge test
x
x
Asthma exacerbation
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
eDiary retrieve/review
x a
x
x
k,u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
eDiary and PEFR z
Twice Daily


Appendix 1: Schedule of Activities
MTPS9579A—Genentech, Inc.
100/Protocol GB41149, Version 4
Screeninga
Run-Inb
Rand.c
Treatment
EOTd
Safety 
Follow
-Up
Safety 
T/Ce
UVf ETg
Day
(Window) –28 to –1
1
15 
(2)
23 
(2)
44 
(3)
72 
(3)
100 
(3)
128 
(3)
156 
(3)
184 
(3)
212 
(3)
240 
(3)
268 
(3)
296 
(3)
324 
(3)
352 
(4)
380
(3)
408 
(3)
Week
4 to 0
0
2
3
6
10
14
18
22
26
30
34
38
42
46
50
54
58
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
ACQ-5 
x
Serum PK sample aa
x q
x
x
x
x
x
x
x
x
x
x
x
Serum sample for 
biomarkers bb
x
x q
x
x
x
x
x
x
Nasosorption for 
biomarkers bb
x
x q
x
x
x
x
x
x
Urine sample for 
biomarkers bb
x
x q
x
x
Serum ADA sample bb, cc
x q
x
x
x
x
x
x
x
x
Blood for SNP bb
x q
Blood for WGS bb, dd
x q
Adverse events ee
x
x
x q
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Study drug 
administration ff
PBO
x q
x
x
x
x
x
x
x
x
x
x
x
Inspection for infusion 
reaction(s)
x
m,q
x
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x m
x
x
x
x


Appendix 1: Schedule of Activities
MTPS9579A—Genentech, Inc.
101/Protocol GB41149, Version 4
ACQ-5 Asthma Control Questionnaire (5 items); ADA anti-drug antibody; eDiaryelectronic diary; EOT end of treatment; ET early termination; 
FeNO fractional exhaled nitric oxide; PBO placebo; PEFRpeak expiratory flow rate; PKpharmacokinetic; PPDpurified protein derivative; 
Rand.randomization; SNPsingle nucleotide polymorphism; TBtuberculosis; UVunscheduled visit; WGSwhole genome sequencing.
Notes:  On treatment days, all assessments should be performed prior to study drug dosing, unless otherwise specified.
a
The screening period may last up to 4 weeks.  The earliest a patient can qualify for the run-in period is after 12 days, when eDiary compliance 
criteria are met.  Patients are allowed one attempt to re-screen.
b
Run-in takes place from Day 1 through Day 14 to assess baseline eDiary symptoms; however, these assessments must be performed on 
Day 1 (2 days).
c
Note that these tests occur on the same day, before (left column) or after (right column) the patient has been randomized.
d
Patients who complete the treatment period will return to the clinic for a treatment completion visit at Week 50.  Patients who discontinue study 
drug for any reason should continue follow-up for all remaining study visits through the end of the study.
e
Final safety follow-up will be conducted by telephone call.
f
Patients who experience symptoms consistent with an asthma exacerbation will be asked to come to the clinic for an unscheduled visit for 
additional evaluations.  Assessments should be performed as clinically indicated.
g Patients who are randomly allocated to the 48-week double-blind treatment period but discontinue study drug should continue follow-up for all 
other study procedures and measurements through the end of the study, except for collection of serum and nasosorption samples for 
biomarkers.  
h Informed consent must be documented before any study-specific screening procedure is performed. 
i
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems.
j
Limited, symptom-directed physical examinations should be performed at specified visits during the placebo-controlled period and as clinically 
indicated.  The examination should include, at a minimum, evaluation of the heart, lungs, and appropriate evaluations based on reported adverse 
events or symptoms.  At the time of each follow-up limited physical examination, an interval medical history should be obtained and any changes 
in medications and allergies should be recorded.
k eDiary compliance must be demonstrated on 5 of 7 days during each of the 2 consecutive weeks of the run-in period.  eDiary compliance less 
than 70% (fewer than 5 out of 7 days/week) during the run-in period will result in study discontinuation.  Patients must meet additional eligibility 
criteria for the double-blind treatment period as outlined in Section 4.1.1.2.
l
Includes respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position (resting for at least 5 minutes), 
and temperature.


Appendix 1: Schedule of Activities
MTPS9579A—Genentech, Inc.
102/Protocol GB41149, Version 4
m Vital signs and a focused physical examination (e.g., for signs of hypersensitivity reaction) will be monitored serially (every 15 [3] minutes) 
during both study drug administration and for the first hour immediately after dosing.  Thereafter, vital signs and a focused physical examination 
will be performed every hour (10 minutes) ending at the investigator’s discretion.
n Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated treatment from 7 days prior to screening (for medications not 
intended for the treatment of asthma) or 3 months prior to screening (for medications intended for the treatment of asthma) to the study 
completion/discontinuation visit.
o Urine drug screen includes, but is not limited to, amphetamines, barbiturates, benzodiazepines, cocaine, cotinine, marijuana/cannabinoids 
(tetrahydrocannabinol), methadone, methamphetamines, methylenedioxymethamphetamine, opiates, and phencyclidine.
p Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).
q Only to be performed after the patient is randomized.
r
Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate or total carbon dioxide (if considered standard of care for 
the region), glucose, BUN or urea, creatinine, calcium, magnesium, phosphate, total protein, albumin, total and direct bilirubin, ALP, ALT, AST, 
urate, LDH, creatinine kinase, and hemoglobin A1c.
s Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, bilirubin, nitrite, blood) and microscopic examination (sediment, 
RBCs, WBCs, casts, crystals, epithelial cells, bacteria).  If urinalysis is abnormal, reflex testing for culture and antibiotic sensitivity should be 
performed if clinically indicated.
t
All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, dosing should be held and a serum pregnancy test performed for confirmation.
u Patients who are not eligible for randomization into the double-blind treatment period should be discontinued from the study.  They are not 
eligible for re-screening.  In addition, these patients should be informed that the first dose given at run-in was a placebo and, therefore, there is 
no additional requirement for follow-up visits.
v Includes hepatitis B surface antibody, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis B DNA (if hepatitis B surface antigen
test is negative and total hepatitis B core antibody test is positive), hepatitis C virus antibody, hepatitis C virus RNA (if hepatitis C virus antibody 
test is positive), and HIV1/2 antibody.
w Patients with a positive PPD test or a QuantiFERONTB Gold test that is positive or indeterminate will require a chest X-ray to review for 
evidence of active TB as described in Section 4.5.11.
x Refer to Section 4.5.6 for FeNO procedure restrictions.


Appendix 1: Schedule of Activities
MTPS9579A—Genentech, Inc.
103/Protocol GB41149, Version 4
y Prohibited medication use prior to spirometry is described in Section 4.4.4.  If the patient has used a bronchodilator within the time window 
defined in Section 4.4.4, then the visit must be rescheduled.  To accommodate the rescheduled visit, the usual visit window during the treatment 
period may be extended to 4 days for Week 2, 5 days for Week 3, and 6 days for all other visits.
z Patients will use an eDiary to record asthma symptoms, PEFR, and use of short-acting rescue therapy twice daily prior to taking asthma 
controller medications.  Refer to Section 4.5.8 for compliance requirements.  The eDiary will remind patients twice daily to complete their entries 
and will provide a time window during which the entry must be completed at approximately the same time each day.  On the days of study visits, 
if the patient has not performed the morning PEFR measurement before arrival at the clinic, the PEFR should be measured at the clinic (see 
Section 4.5.8.2).
  
aa On all study drug administration days that require PK serum sampling, PK samples will be obtained pre-dose and post-dose (2 hours 
30 minutes after the end of the dose).  On clinic visit days where study drug is not administered and PK serum sampling is required, only one 
PK sample is to be obtained.
bb To be collected predose.
cc Samples will also be used for PK and biomarker analyses.
dd Not applicable for a site that has not been granted approval for WGS.
ee After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 84 days after the final dose of study drug or 
end of study (Week 58) for patients who discontinue study drug but remain on study, whichever occurs later, or 6 weeks following the placebo 
dose for patients who failed to be randomized. After this period, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  
ff Patients should be administered the study drug over 1 hour, and observed for 1 hour post-infusion, with observation ending at the investigator’s 
discretion (as described in footnote “m”).


MTPS9579A—Genentech, Inc.
104/Protocol GB41149, Version 4
Appendix 2
Asthma Control Questionnaire, 5-Item Version


Appendix 2: Asthma Control Questionnaire, 5-Item Version
MTPS9579A—Genentech, Inc.
105/Protocol GB41149, Version 4


Appendix 2: Asthma Control Questionnaire, 5-Item Version
MTPS9579A—Genentech, Inc.
106/Protocol GB41149, Version 4


MTPS9579A—Genentech, Inc.
107/Protocol GB41149, Version 4
Appendix 3
Tuberculosis Worksheet
Patient: __________________________________________
Visit: 1 (Screening)
Person completing form: _____________________________
Date: _______________
Patient must have either a purified protein derivative (PPD) or QuantiFERON TB Gold test per 
exclusion criteria in protocol Section 4.1.2.  Please answer the following for potential patients per 
the information recorded in the source document.
1.1 Does the patient have active tuberculosis? 

No.  Continue to 2.1. 

Yes. Stop – this patient must be excluded from the study.
2.1 If the patient had a PPD test, is the result negative (5 mm induration at 48 to 72 hours after 
the test was placed) or positive (5 mm induration at 48 to 72 hours after the test was placed)?

Negative.  Patient is eligible per exclusion criterion in protocol Section 4.1.2. 

Positive.  Continue to 2.2. 

N/A.  Patient had QuantiFERON TB Gold test instead of a PPD.  Continue to 2.3. 
2.2 Does patient have a history of bacille Calmette-Guérin (BCG) vaccination?

Yes.  Patient should have a QuantiFERON TB Gold test performed.  After QuantiFERON 
results are available, continue to 2.3.

No/Unknown.  Continue to 3.1.
2.3 What is the result of the QuantiFERON TB Gold test?

Negative.  Patient is eligible per exclusion criterion in protocol Section 4.1.2. 

Indeterminate or Positive.  Continue to 3.1. 
3.1 Does the patient currently have any of the following symptoms? 

Productive, prolonged cough (3 weeks) 

Coughing up blood 

Fever 

Night sweats 

Unexplained appetite loss 

Unintentional weight loss

No.  Continue to 3.2. 

Yes. Stop – this patient must be excluded from the study.
______________________________
_______________________________
___________
Person assessing item 3.1
Signature
Date
3.2 Does the patient have a documented history of adequate prophylaxis (completed course for 
latent tuberculosis per the treatment options as stated in the WHO guidelines; WHO 2018)? 

Yes.  Continue to 3.3. 


Appendix 3: Tuberculosis Worksheet
MTPS9579A—Genentech, Inc.
108/Protocol GB41149, Version 4

No.  Stop – this patient must be excluded from the study.
3.3 Has the patient had any known exposure to a case of active tuberculosis since their most 
recent prophylaxis?

Yes.  Stop – the patient must be excluded from the study.

No.  Continue to 3.4.
3.4 Has the patient had a chest radiograph or CT scan within 3 months prior to screening?

No.  A chest radiograph should be performed per protocol Section 4.5.12, and continue to 
3.5.

Yes.  Continue to 3.5.
3.5 Is there evidence of active tuberculosis on the chest radiograph or CT?

No.  Patient is eligible per exclusion criterion in protocol Section 4.1.2.

Yes.  Stop – this patient must be excluded from the study.


MTPS9579A—Genentech, Inc.
109/Protocol GB41149, Version 4
Appendix 4
Daytime eDiary 
Please answer the following questions first thing in the morning. These 
questions ask about your asthma after you went to sleep last night.
1. How severe were your asthma symptoms after going to sleep last night 
(shortness of breath, cough, wheeze, or chest tightness)?  
I had no asthma symptoms after going to sleep last night 
Mild
Moderate
Severe
Very Severe
2. After going to sleep last night, did you wake up because of your asthma 
symptoms (shortness of breath, cough, wheeze, or chest tightness)?
No
Yes
3. After going to sleep last night, did you take any rescue medication for your 
asthma symptoms (shortness of breath, cough, wheeze, or chest 
tightness)? 
No, I did not take any rescue medication
Yes, I used a rescue inhaler 
How many puffs of a rescue inhaler did you take?  ______   puffs
Yes, I used a nebulizer (breathing machine)
How many times did you use a nebulizer (breathing machine)?  
________ times


MTPS9579A—Genentech, Inc.
110/Protocol GB41149, Version 4
Appendix 5
Nighttime eDiary 
Please answer the following questions in the evening, just before bedtime. 
These questions ask about your asthma today, from waking up until now.
1. How severe were your asthma symptoms today (shortness of breath, 
cough, wheeze, or chest tightness)?  
I had no asthma symptoms today 
Mild
Moderate
Severe
Very Severe
2. Did you take any rescue medication for your asthma symptoms today 
(shortness of breath, cough, wheeze, or chest tightness)? 
No, I did not take any rescue medication
Yes, I used a rescue inhaler 
How many puffs of a rescue inhaler did you take?  ______   puffs
Yes, I used a nebulizer (breathing machine)
How many times did you use a nebulizer (breathing machine)?  
______ times


MTPS9579A—Genentech, Inc.
111/Protocol GB41149, Version 4
Appendix 6
Anaphylaxis Precautions and Diagnosis
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures.
The following equipment is needed in the event of a suspected anaphylactic reaction 
during study drug infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for intravenous, intramuscular, and endotracheal administration in 
accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
The following are the procedures to follow in the event of a suspected anaphylactic 
reaction during study drug infusion:

Stop the study drug infusion. 

Call for additional medical assistance.

Maintain an adequate airway.

Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible.

Administer antihistamines, epinephrine, or other medications as required by patient 
status and as directed by the physician in charge.

Continue to observe the patient and document observations.

Draw serum/plasma samples for immunogenicity testing.

Ask patient to return for washout immunogenicity sample if appropriate.


Appendix 6: Anaphylaxis Precautions and Diagnosis 
MTPS9579A—Genentech, Inc. 
112/Protocol GB41149, Version 4 
 
Criteria for Anaphylaxis Diagnosis 
Anaphylaxis is highly likely when any one of the following criteria are fulfilled (adapted 
from Sampson et al. 2006): 
1. Acute onset of an illness (minutes to several hours) with involvement of the 
skin, mucosal tissue, or both (e.g., generalized hives, pruritis or flushing, 
swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, 
stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely 
allergen for that patient (minutes to several hours): 
 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-
flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, 
stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], 
syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy, abdominal pain, 
vomiting) 
 
Reference: 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report⎯Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117:391−7. 


 
MTPS9579A—Genentech, Inc. 
113/Protocol GB41149, Version 4 
Appendix 7  
WHO Toxicity Grading Scale 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
HEMATOLOGY 
Hemoglobin 
9.5−10.5 g/dL 
8.0−9.4 g/dL 
6.5−7.9 g/dL 
< 6.5 g/dL 
Absolute neutrophil count 
1000−1500/mm3 
750−999/mm3 
500−749/mm3 
<500/mm3 
Platelets 
75,000−99,000/mm3 
50,000−74,999/mm3 
20,000−49,000/mm3 
<20,000/mm3 
PT 
1.01−1.25 × ULN 
1.26−1.5 × ULN 
1.51−3.0 × ULN 
>3 × ULN 
aPPT 
1.01−1.66 × ULN 
1.67−2.33 × ULN 
2.34−3 × ULN 
> 3 × ULN 
Fibrinogen 
0.75−0.99 × LLN 
0.50−0.74 × LLN 
0.25−0.49 × LLN 
< 0.25 × LLN 
Fibrin split product 
20−40 μg/mL 
41−50 μg/mL 
51−60 μg/mL 
> 60 μg/mL 
Methemoglobin 
5%−9.9% 
10.0%−14.9% 
15.0%−19.9% 
> 20% 
LIVER ENZYMES 
AST (SGOT) 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
ALT (SGPT) 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
GGT 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
ALP 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
Amylase 
1.1−1.5 × ULN 
1.6−2.0 × ULN 
2.1−5.0 × ULN 
> 5.1 × ULN 
CHEMISTRIES 
Hyponatremia 
130−135 mEq/L 
123−129 mEq/L 
116−122 mEq/L 
< 116 or mental status changes or 
seizures 
Hypernatremia 
146−150 mEq/L 
151−157 mEq/L 
158−165 mEq/L 
> 165 mEq/L or mental status 
changes or seizures 
Hypokalemia 
3.0−3.4 mEq/L 
2.5−2.9 mEq/L 
2.0−2.4 mEq/L or intensive 
replacement Rx required or 
hospitalization required 
< 2.0 mEq/L or paresis or ileus or 
lifethreatening arrhythmia 
Hyperkalemia 
5.6−6.0 mEq/L 
6.1−6.5 mEq/L 
6.6−7.0 mEq/L 
> 7.0 mEq/L or lifethreatening 
arrhythmia 
Hypoglycemia 
55−64 mg/dL 
40−54 mg/dL 
30−39 mg/dL 
<30 mg/dL or mental status changes 
or coma 
Hyperglycemia 
(note if fasting) 
 
 
251−500 mg/dL 
> 500 mg/dL or ketoacidosis or 
seizures 


Appendix 7: WHO Toxicity Grading Scale 
 
MTPS9579A—Genentech, Inc. 
114/Protocol GB41149, Version 4 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Hypocalcemia 
(corrected for albumin) 
8.4−7.8 mg/dL 
7.7−7.0 mg/dL 
6.9−6.1 mg/dL 
< 6.1 mg/dL or lifethreatening 
arrhythmia or tetany 
Hypercalcemia 
(correct for albumin) 
10.6−11.5 mg/dL 
11.6−12.5 mg/dL 
12.6−13.5 mg/dL 
> 13.5 mg/dL lifethreatening 
arrhythmia 
Hypomagnesemia 
1.4−1.2 mEq/L 
1.1−0.9 mEq/L 
0.8−0.6 mEq/L 
< 0.6 mEq/L or lifethreatening 
arrhythmia 
Hypophosphatemia 
2.0−2.4 mg/dL 
1.5 −1.9 mg/dL or 
replacement Rx 
required 
1.0 −1.4 mg/dL intensive 
Rx or hospitalization 
required 
< 1.0 mg/dL or lifethreatening 
arrhythmia 
Hyperbilirubinemia 
1.1−1.5 × ULN 
1.6−2.5 × ULN 
2.6−5 × ULN 
> 5 × ULN 
BUN 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
Creatinine 
1.1 × 1.5 × ULN 
1.6−3.0 × ULN 
3.1−6 × ULN 
> 6 × ULN or required dialysis 
URINALYSIS 
Proteinuria 
1+ or  
< 0.3% or  
<3 g/L or  
200 mg−1 g loss/day 
2 −3 + or  
0.3%−1.0% or 
3−10 g/L or  
1−2 g loss/day 
4+ or 
> 1.0% or 
> 10 g/L or 
2−3.5 g loss/day 
nephrotic syndrome or  
> 3.5 g loss/day 
Hematuria 
Microscopic only 
Gross, no clots 
Gross+ clots 
Obstructive or required transfusion 
CARDIAC DYSFUNCTION 
Cardiac rhythm 
 
Asymptomatic, 
transient signs, no 
Rx required 
Recurrent/persistent; 
no Rx required 
Requires treatment 
Hypertension 
Transient inc. > 20 mm; 
no Rx 
Recurrent, chronic, 
> 20 mm, Rx required 
Requires acute Rx; 
no hospitalization 
Requires hospitalization 
Hypotension 
Transient orthostatic 
hypotension, no Rx 
Symptoms correctable 
with oral fluids Rx 
Requires IV fluids; 
no hospitalization 
required 
Requires hospitalization 
Pericarditis 
Minimal effusion 
Mild/moderate 
asymptomatic 
effusion, no Rx 
Symptomatic effusion; pain; 
EKG changes 
Tamponade; pericardiocentesis or 
surgery required 


Appendix 7: WHO Toxicity Grading Scale 
 
MTPS9579A—Genentech, Inc. 
115/Protocol GB41149, Version 4 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Hemorrhage, blood loss 
Microscopic/occult 
Mild, no transfusion 
Gross blood loss; 
1−2 units transfused 
Massive blood loss; 
> 3 units transfused 
RESPIRATORY 
Cough 
Transient; no Rx 
Treatment associated 
cough; local Rx 
Uncontrolled 
 
Bronchospasm, acute 
Transient; no Rx 
< 80%−70% FEV1 
(or peak flow) 
Requires Rx 
normalizes with 
bronchodilator; FEV1 
50%−70% (or peak 
flow) 
No normalization with 
bronchodilator; FEV1 
25%−50% (or peak flow 
retractions) 
Cyanosis: FEV1 < 25% (or peak 
flow) or intubated 
GASTROINTESTINAL 
Stomatitis 
Mild discomfort; 
no limits on activity 
Some limits on 
eating/drinking 
Eating/talking very limited 
Requires IV fluids 
Nausea 
Mild discomfort; 
maintains reasonable 
intake 
Moderate discomfort; 
intake decreased 
significantly; some 
activity limited 
Severe discomfort; 
no significant intake; 
activities limited 
Minimal fluid intake 
Vomiting 
Transient emesis 
Occasional/moderate 
vomiting 
Orthostatic hypotension or 
IV fluids required 
Hypotensive shock or hospitalization
required for IV fluid therapy 
Constipation 
Mild 
Moderate 
Severe 
Distensions with vomiting 
Diarrhea 
Transient 3−4 loose 
stools/day 
5−7 loose stools/day 
Orthostatic hypotension or
> 7 loose stools/day or 
required IV fluids 
Hypotensive shock or hospitalization 
for IV fluid therapy required 
NEURO & NEUROMUSCULAR 
Neuro−cerebellar 
Slight incoordination 
dysdiadochokinesis 
Intention tremor, 
dysmetria, slurred 
speech; nystagmus 
Locomotor ataxia 
Incapacitated 
Mood 
Mild anxiety or 
depression 
Moderate anxiety or 
depression and 
therapy required 
Severe anxiety or 
depression or mania; needs 
assistance 
Acute psychosis; incapacitated, 
requires hospitalization 


Appendix 7: WHO Toxicity Grading Scale 
 
MTPS9579A—Genentech, Inc. 
116/Protocol GB41149, Version 4 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Neuro control 
Mild difficulty 
concentrating; 
no Rx; mild 
confusion/agitation; 
ADL unaffected 
Moderate 
confusion/agitation 
some limitation of 
ADL; minimal Rx 
Severe confusion/agitation 
needs assistance for ADL; 
therapy required 
Toxic psychosis; hospitalization 
Muscle strength 
Subjective weakness; 
no objective 
symptoms/signs 
Mild objective 
signs/symptoms; 
no decrease in 
function 
Objective weakness 
function limited 
Paralysis 
OTHER PARAMETERS 
Fever: oral, > 12 hours 
37.7°C −38.5°C or 
100.0°F −101.5°F 
38.6°C −39.5°C or 
101.6°F −102.9°F 
39.6°C −40.5°C or 
103°F −105°F 
> 40°C or > 105°F 
Headache 
Mild, no Rx therapy 
Transient, moderate; 
Rx required 
Severe; responds to initial 
narcotic therapy 
Intractable; required repeated 
narcotic therapy 
Fatigue 
No decrease in ADL 
Normal activity 
decreased 25%−50% 
Normal activity 
decreased > 50% can’t 
work 
Unable to care for self 
Allergic reaction 
Pruritus without rash 
Localized urticaria 
Generalized urticaria; 
angioedema 
Anaphylaxis 
Local reaction 
Tenderness or 
erythema 
Induration < 10 cm or 
phlebitis or 
inflammation 
Induration > 10 cm or 
ulceration 
Necrosis 
Mucocutaneous 
Erythema; pruritus 
Diffuse, 
maculopapular rash, 
dry desquamation 
Vesiculation, moist 
desquamation, or ulceration
Exfoliative dermatitis, mucous 
membrane involvement or erythema, 
multiforme or suspected 
StevensJohnson or necrosis 
requiring surgery 
ADL = activities of daily living; FEV1= forced expiratory volume in 1 second; LLN= lower limit of normal; Rx= treatment; ULN= upper 
limit of normal. 



SAP_001.pdf: 
 
Official Title: 
A Phase IIa, Multicenter, Randomized, Placebo-Controlled, Double-
Blind Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of 
MTPS9579A in Patients with Asthma Requiring Inhaled 
Corticosteroids and a Second Controller 
NCT Number: 
NCT04092582 
Document Date: 
DAP Version 3: 30-July-2022 
 
 
 


 
Output Specifications 
Study title: 
A PHASE IIa, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF MTPS9579A IN PATIENTS 
WITH ASTHMA REQUIRING INHALED 
CORTICOSTEROIDS AND A SECOND CONTROLLER 
Protocol number: 
GB41149 
Reporting event: 
CSR, August 2022 
Author: 
 
  
July 21, 
2022  
Study Statistician 
  
  
Date 
Approver: 
  
  
 
  
 July 30, 2022 
 
  
Date 


 
  
  
* The approver has ensured that key team members have been involved, 
contributed, and reviewed the Output Specifications for completeness and 
ability to address the scientific objectives and reporting needs, as well as for 
appropriate level of scope. 
 
 
 
 
Key Definitions: 
Analysis Populations 
Intent-to-Treat (ITT) Population: 
Definition: All patients who are randomized in the study.  
Variable: ADSL.ITFL 
 
Modified Intent-to-Treat (mITT) Population: 
Definition: All patients randomized who received at least one dose of study drug. 
Variable: ADSL.MITTFL 
 
Run-in Safety-Evaluable (PEFL) Population: 
Definition: All patients who received the single-blind placebo dose during the run-in period, regardless 
of whether or not the patient is randomly allocated into the double-blind treatment period. 
Variable: ADSL.PEFL 
 
Safety-Evaluable (SE) Population: 
Definition: All randomized patients who received at least one dose of study drug during the 48-week 
double-blind treatment period, with patients grouped according to treatment received (MTPS9579A or 
placebo) 
Variable: ADSL.SAFFL  
 


Biomarker Subgroups 
● NASO 
● SERUM 
Definition of Baseline 
Use randomization (Week 2) as the baseline. 
● ADLB uses VISIT = "WEEK 2-RANDOMIZATION" for Baseline calculations; use VISIT = 
"SCREENING" for parameters that don't have  VISIT = "WEEK 2-RANDOMIZATION" . 
● ADVS uses VISIT = "WEEK 2-RANDOMIZATION" and VSTPT = "PRE-DOSE" for Baseline 
calculations or  VISIT = "SCREENING" for parameters that don't have  VISIT = "WEEK 2-
RANDOMIZATION" (height and weight). 
Data Handling Specifications: 
  
General Output Specification Categories for all TLGs unless specified below: 
●   
Column Variables:  
All outputs are unblinded. Columns are displayed in this order: ‘Placebo’, ‘MTPS9579A’. 
●   
Treatment Group: Group by Treatment Assigned. ADSL.TRT01P 
●   
Column Totals: ‘All Patients’ 
●   
Analysis Variables: See each mock-up below. 
●   
Numeric Precision and Formatting of Statistics: Round to 1 decimal unless 
otherwise specified. For change from baseline outputs, using default STREAM precision is 
fine. 
●   
Optional Subsetting: N 
 
 
Section 1. Study Conduct and Analysis Population 
Output 1.1 Summary of Analysis Populations (APT01) 
 
Analysis Populations, Placebo Run-in Period, All Patients 
Protocol: GB41149 
  ________________________________________________________ 
                                              All Patients 
                                                (N=140)    
  ________________________________________________________ 
  Run-in Safety-Evaluable (PEFL) Population     
140 ( 100%)  
  ________________________________________________________   
 
Analysis Populations, All Patients 
Protocol: GB41149 
























Output 2.6 Listing of Medical History (MHL01) 
Protocol: GB41149 
Analysis Population: Run-in safety-evaluable population (PEFL)                                                     
  Treatment: ARM A                                                                                                                     
  ___________________________________________________________________________________________________________________ 
                                                                                                                      
  Center/Patient ID - Age/Sex/Race       Date of First   Start Date  Start Day  End Date   End Day                    
  Body System or Organ Class               Study Drug    of             of      of           of     Time Relation     
    Standardized Disease Term            Administration  Disease      Disease   Disease    Disease  of Disease        
  ___________________________________________________________________________________________________________________ 
                                                                                                                      
 
 - 
/F/
                                                                                                             
  GASTROINTESTINAL DISORDERS                                                   
                                              
    GASTROINTESTINAL HAEMORRHAGE          
  
    -2021   
  -2010   prior             
    DUODENAL ULCER                        
  
    -2016   
  -1996   prior             
  INFECTIONS AND INFESTATIONS             
  
            
                                             
    CHRONIC HEPATITIS C                   
  
    -3758   
          prior-concomitant 
  MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS      
            
                                             
    HAEMARTHROSIS                         
  
            
  -2338   prior             
    OSTEOARTHRITIS                        
  
    -2348   
          prior-concomitant 
    OSTEOARTHRITIS                        
  
    -1133   
          prior-concomitant 
  No Coding available                     
  
            
                                             
    No Coding available                   
  
    -2018   
                            
  RENAL AND URINARY DISORDERS             
  
            
                                             
    STAG HORN CALCULUS                    
  
    -5574   
  -5571   prior             
  SURGICAL AND MEDICAL PROCEDURES         
  
            
                                             
    HIP ARTHROPLASTY                      
  
            
  -2338   prior             
    RENAL STONE REMOVAL                   
  
    -5574   
  -5571   prior             
                                                                                                                      
  
 - 
/M/
                                                                                                             
  No Coding available                                                                                                                  
    No Coding available                    
     
     -6447                                          
                                                                                                                      
  
 - 
/F/
                                                                                                             
  No Coding available                                                                                                                  
    No Coding available                    
     
     -7739                                          
                                                                                                                      
  ___________________________________________________________________________________________________________________                  
  Investigator text for medical history conditions coded using MedDRA xx.x.                                                            
  * End day derived from imputed end date.                                                                           
 
Output 2.7 Glossary of Medical History Coded Terms (AEL01_NOLLT) 
Protocol: GB41149 
Analysis Population: Run-in safety-evaluable population (PEFL) 
                                                                                                                                     
  MedDRA System Organ Class                         
 
MedDRA Preferred Term              
 
Investigator-
Specified Medical History Term    
__________________________________________________________________________________________________                               
  BLOOD AND LYMPHATIC SYSTEM DISORDERS             
IRON DEFICIENCY ANAEMIA            
IRON 
DEFICIENCY ANAEMIA                          
  CONGENITAL, FAMILIAL AND GENETIC DISORDERS          ARNOLD-CHIARI MALFORMATION              ARNOLD 
CHIARI                                    
                                                     
 
 
 
GILBERT'S SYNDROME      
 
GILBERT'S 
SYNDROME                               


  ENDOCRINE DISORDERS                               
 
HYPOTHYROIDISM                   
 
 
HYPOTHYROID                                      
  … 
 
 
 
 
 
 
… 
 
 
 
 
….  
__________________________________________________________________________________________________ 
 
Section 3. Efficacy Analysis 
Efficacy analyses will be conducted on an mITT population, consisting of all randomized patients who 
received at least one dose of study drug during the 48-week double-blind treatment period, with 
patients grouped according to the treatment assigned at randomization. 
 
Unless otherwise noted, analyses of efficacy outcome measures will be adjusted by: 
1. Blood eosinophil level at week 2 randomization visit (ADSL.BEOGRWK2 < 150 cells/μL, 
150−300 cells/μL, > 300 cells/μL)  
2. Geographic region (ADSL.REGIONST: United States/Western Europe, Eastern Europe, 
Southern Hemisphere) 
3. Asthma exacerbations in prior year (ADSL.ASMEXGST) 
 
Tables 
Output 3.1 Time to First CompEx Event, 48-Week Double-Blind Treatment 
Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (MITTFL = ‘Y’) 
 
Time to First CompEx Event, 48−Week Double−Blind Treatment Period, mITT Subjects Who Were 
Dosed in Treatment Period 
 
Placebo 
MTPS9579A Active 
Total number of patients per arm 
XX 
XX 
 
 
 
Patients with event: N (%)  
XX (XX.X%) 
XX (XX.X%) 
    Patients with diary event: N (%) 
XX (XX.X%) 
XX (XX.X%) 
    Patients with exacerbation: N (%)  
XX (XX.X%) 
XX (XX.X%) 
Patients without event (%)  
XX (XX.X%) 
XX (XX.X%) 
 
 
 
Time to event (weeks)  
 
 


    Median 
XXX.X 
XXX.X 
        95% CI 
(XXX, XXX) 
(XXX, XXX) 
    25 - 75 percentile 
XXX, XXX 
XXX, XXX    
    Range  
XXX to XXX 
XXX to XXX 
 
 
 
Stratified Analysis 
 
 
    p-value (log-rank)  
- 
X.XXXX 
 
 
 
Hazard Ratio  
- 
X.XX 
    95% CI 
- 
(XX.X, XX.X) 
    p-value 
- 
X.XXXX 
Hazard ratios were estimated by Cox regression with the following stratification factors as covariates: 
blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma 
exacerbations requiring the use of systemic corticosteroids within the 12 months prior to the study 
entry (1 or >=2 events), and geographic region (United States/Western Europe [United States, 
Germany], Eastern Europe [Poland], Southern Hemisphere [Peru, Argentina]). 
 
Output 3.2 Time to First Protocol-Defined Asthma Exacerbation, 48-Week 
Double-Blind Treatment Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (MITTFL = ‘Y’) 
 
Time to First Protocol-defined Asthma Exacerbation, 48−Week Double−Blind Treatment Period, mITT 
Subjects Who Were Dosed in Treatment Period 
 
Placebo 
MTPS9579A Active 
Total number of patients per arm 
XX 
XX 
 
 
 
Patients with event (%) 
XX (XX.X%) 
XX (XX.X%) 
Patients without event (%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 
Time to event (weeks) 
 
 
    Median 
XXX.X 
XXX.X 
        95% CI 
(XXX, XXX) 
(XXX, XXX) 


    25 - 75 percentile 
XXX, XXX 
XXX, XXX    
    Range  
XXX to XXX 
XXX to XXX 
 
 
 
Stratified Analysis 
 
 
    p-value (log-rank) 
- 
X.XXXX 
 
 
 
Hazard Ratio 
- 
X.XX 
    95% CI 
- 
(XX.X, XX.X) 
    p-value 
- 
X.XXXX 
Hazard ratios were estimated by Cox regression with the following stratification factors as covariates: 
blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma 
exacerbations requiring the use of systemic corticosteroids within the 12 months prior to the study 
entry (1 or >=2 events), and geographic region (United States/Western Europe [United States, 
Germany], Eastern Europe [Poland], Southern Hemisphere [Peru, Argentina]). 
 
Output 3.3 Rate of Asthma Exacerbations, 48-Week Double-Blind 
Treatment Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (MITTFL = ‘Y’) 
 
Rate of Protocol-defined Asthma Exacerbation, 48−Week Double−Blind Treatment Period, All mITT Subjects 
Who Were Dosed in Treatment Period 
 
Placebo 
MTPS9579A Active 
 
 
 
N 
XXX 
XXX 
Number of exacerbations per patient 
 
 
0 XX (XX.X%) 
XX (XX.X%) 
1 XX (XX.X%) 
XX (XX.X%) 
2 XX (XX.X%) 
XX (XX.X%) 
3 XX (XX.X%) 
XX (XX.X%) 
… 
 
 
 
 
 
Total number of exacerbations 
XXX 
XXX 


Total follow-up time at risk (years) 
XXX.X 
XXX.X 
 
 
 
Exacerbation rate (per year) 
 
 
    Unadjusted 
X.XX 
X.XX 
    Adjusted 
X.XX 
X.XX 
 
 
 
Absolute rate difference (events/ year), 
adjusted (MTPS9579A - placebo) 
– 
X.XX 
 
 
 
Rate ratio, adjusted 
(MTPS9579A/placebo) 
– 
X.XX 
    95% CI 
 
(X.XX, X.XX) 
    p-value 
– 
X.XXXX 
Percentage rate reduction, adjusted 
(MTPS9579A vs. placebo) 
– 
(XX.X%) 
Adjusted exacerbation rates and rate ratio are estimated from a Poisson regression model with over-
dispersion adjusted for the following covariates and log(patient time at risk) as offset term: blood 
eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma exacerbations 
requiring the use of systemic corticosteroids within the 12 months prior to the study entry (1 or >=2 
events), and geographic region (United States/Western Europe [United States, Germany], Eastern 
Europe [Poland], Southern Hemisphere [Peru, Argentina]). 
 
Output 3.4 Pre-Bronchodilator FEV1 Results and Change from Baseline by 
Visit (L), 48-Week Double-Blind Treatment Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FEV1_MITT = ‘Y’) 
 
Pre−Bronchodilator FEV1 Results and Change from Baseline by Visit (L), 48−Week Double−Blind 
Treatment Period, mITT Subjects Who Were Dosed in Treatment Period 
 
 
 
Placebo 
(N = XXX) 
MTPS9579A Active 
(N = XXX)  
Baseline 
Value at visit 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 


 
 
 
 
 
Week 3 
Value at visit 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Change from baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Percent change from 
baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Median 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Min - Max 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
 
 
 
Week ... 
 
 
 
 
 
 
 
 
 
Week 50 
Value at visit 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Change from baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Percent change from 
baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 


 
 
Median 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Min - Max 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Output 3.5 Pre-Bronchodilator FeNO Results and Change from Baseline 
by Visit (ppb), 48-Week Double-Blind Treatment Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FENO_MITT = ‘Y’) 
 
Pre-Bronchodilator FeNO Results and Change from Baseline by Visit (ppb), 48−Week Double−Blind 
Treatment Period, mITT Subjects Who Were Dosed in Treatment Period 
 
 
 
Placebo 
(N = XXX) 
MTPS9579A Active 
(N = XXX) 
Baseline 
Value at visit 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
Week 3 
Value at visit 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Change from baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Percent change from 
baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Median 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Min - Max 
XX.X (XX.X) 
XX.X (XX.X) 


 
 
 
 
 
Week ... 
 
 
 
 
 
 
 
 
 
Week 50 
Value at visit 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Change from baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Percent change from 
baseline 
n 
XXX 
XXX 
 
 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Median 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Min - Max 
XX.X (XX.X) 
XX.X (XX.X) 
 
Output 3.6 Mixed-Effect Model Repeated Measures Analysis of Absolute 
Change from Randomization Visit in Pre-bronchodilator FEV1 (L) through 
Week 50 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FEV1_MITT = ‘Y’) 
 
Mixed-Effect Model Repeated Measures Analysis of Absolute Change from Randomization Visit in 
Pre-bronchodilator FEV1 (L) through Week 50, mITT Subjects Who Were Dosed in Treatment Period 
Visit 
Absolute Change from Baseline, 
Pre−Bronchodilator FEV1 (L) 
Placebo 
(N = XXX) 
MTPS9579A Active 
(N = XXX) 
Week 3 
n 
XXX 
XXX 
 
Adjusted Mean (SE) 
XXX (XX) 
XXX (XX) 
 
95% CI for Adjusted Mean 
(XXX, XXX) 
(XXX, XXX) 
 
Difference in Adjusted Means (SE) 
- 
XXX (XX) 


 
95% CI for Difference in Adjusted Means 
- 
(XXX, XXX) 
 
P-value 
- 
X.XXXX 
 
 
 
 
Week ... 
 
 
 
 
 
 
 
Week 50 
n 
XXX 
XXX 
 
Adjusted Mean (SE) 
XXX (XX) 
XXX (XX) 
 
95% CI for Adjusted Mean 
(XXX, XXX) 
(XXX, XXX) 
 
Difference in Adjusted Means (SE) 
- 
XXX (XX) 
 
95% CI for Difference in Adjusted Means 
- 
(XXX, XXX) 
 
P-value 
- 
X.XXXX 
Footnotes: Estimates are based on a mixed model for repeated measures (MMRM) analysis with an 
unstructured covariance matrix. The model used the absolute change pre-bronchodilator FEV1 as the 
response variable and included terms for treatment arm, study visit, treatment arm by study visit 
interaction, baseline FEV1 as well as its interaction with study visit, in addition to the stratification 
factors: blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma 
exacerbations requiring the use of systemic corticosteroids within the 12 months prior to the study 
entry (1 or >=2 events), and geographic region (United States/Western Europe [United States, 
Germany], Eastern Europe [Poland], Southern Hemisphere [Peru, Argentina]). Subjects without valid 
baseline values are excluded from analysis. 
N in the header represents the number of subjects with at least one post-baseline value. 
 
 
Output 3.7 Mixed-Effect Model Repeated Measures Analysis of Relative 
Change from Randomization Visit in Pre-bronchodilator FEV1 (L) through 
Week 50 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FEV1_MITT = ‘Y’) 
 
Similar to Output 3.6. 
Output 3.8 Mixed-Effect Model Repeated Measures Analysis of Absolute 
Change from Randomization Visit in FeNO (ppb) through Week 50 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FENO_MITT = ‘Y’) 


 
Mixed-Effect Model Repeated Measures Analysis of Absolute Change from Randomization Visit in 
Pre-bronchodilator FeNO (ppb) through Week 50, mITT Subjects Who Were Dosed in Treatment 
Period 
Visit 
Absolute Change from Baseline, 
Pre−Bronchodilator FeNO (ppb) 
Placebo 
(N = XXX) 
MTPS9579A Active 
(N = XXX) 
Week 3 
n 
XXX 
XXX 
 
Adjusted Mean (SE) 
XXX (XX) 
XXX (XX) 
 
95% CI for Adjusted Mean 
(XXX, XXX) 
(XXX, XXX) 
 
Difference in Adjusted Means (SE) 
- 
XXX (XX) 
 
95% CI for Difference in Adjusted Means 
- 
(XXX, XXX) 
 
P-value 
- 
X.XXXX 
 
 
 
 
Week ... 
 
 
 
 
 
 
 
Week 50 
n 
XXX 
XXX 
 
Adjusted Mean (SE) 
XXX (XX) 
XXX (XX) 
 
95% CI for Adjusted Mean 
(XXX, XXX) 
(XXX, XXX) 
 
Difference in Adjusted Means (SE) 
- 
XXX (XX) 
 
95% CI for Difference in Adjusted Means 
- 
(XXX, XXX) 
 
P-value 
- 
X.XXXX 
Footnotes: Estimates are based on a mixed model for repeated measures (MMRM) analysis with an 
unstructured covariance matrix. The model used the absolute change pre-bronchodilator FeNO as 
the response variable and included terms for treatment arm, study visit, treatment arm by study visit 
interaction, baseline FeNO as well as its interaction with study visit, in addition to the stratification 
factors: blood eosinophil level at visit 1 (<150, >=150 to <=300, >300 cells/uL), number of asthma 
exacerbations requiring the use of systemic corticosteroids within the 12 months prior to the study 
entry (1 or >=2 events), and geographic region (United States/Western Europe [United States, 
Germany], Eastern Europe [Poland], Southern Hemisphere [Peru, Argentina]). 
N in the header represents the number of subjects with at least one post-baseline value. 
 
Output 3.8 Mixed-Effect Model Repeated Measures Analysis of Relative 
Change from Randomization Visit in FeNO (ppb) through Week 50 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FENO_MITT = ‘Y’) 


 
Similar to Output 3.7. 
Graphs 
Output 3.9 Time to First CompEx Event, 48-Week Double-Blind Treatment 
Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (MITTFL = ‘Y’) 
 
Kaplan Meier Plot of Time to First CompEx Event, 48−Week Double−Blind Treatment Period, mITT Subjects 
Who Were Dosed in Treatment Period 
 
 
Output 3.10 Time to First Protocol-Defined Asthma Exacerbation, 48-Week 
Double-Blind Treatment Period 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (MITTFL = ‘Y’) 
 
Kaplan Meier Plot of Time to First Protocol-defined Asthma Exacerbation, 48−Week Double−Blind Treatment 
Period, mITT Subjects Who Were Dosed in Treatment Period 
 
 
 
Output 3.11 Absolute Change from Randomization in Pre-bronchodilator 
FEV1 (L) Across Time 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FEV1_MITT) 
 
Note: add the number of patients at each time point in the plot. Considering the applicability of SAS, a separate 
table placed below the plot is also acceptable. 
Output 3.12 Relative Change from Randomization in Pre-bronchodilator 
FEV1 (%) Across Time 
Protocol: GB41149 
Analysis Population: Modified Intent-to-treat population (FENO_MITT) 
 
Similar to Output 3.11. 


















Output 4.9 Adverse Events Leading to Study Discontinuation (AET02) 
Protocol: GB41149 
Analysis Population: 48-Week Double-Blind Treatment Period; Safety-evaluable population 
 
[Similar to output 4.7] 
 
Output 4.10 Serious Adverse Events (AET02) 
Protocol: GB41149 
Analysis Population: 
(1) Placebo Run-in Period; Run-in safety-evaluable population (PERIOD1_PEFL) 
(2) 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-evaluable 
population (PERIOD2_SE) 
 
[Similar to output 4.7] 
Output 4.11 Adverse Events Related to Study Treatment (AET09) 
Protocol: GB41149 
Analysis Population:  
(1) Placebo Run-in Period; Run-in safety-evaluable population (PERIOD1_PEFL) 
(2) 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-evaluable 
population (PERIOD2_SE) 
 
[Similar to output 4.7] 
 
Output 4.12 Serious Adverse Events Related to Study Treatment (AET02) 
Protocol: GB41149 
Analysis Population:  
(1) Placebo Run-in Period; Run-in safety-evaluable population (PERIOD1_PEFL) 
(2) 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-evaluable 
population (PERIOD2_SE) 
 
[Similar to output 4.7] 
 
Output 4.13 Adverse Events by Preferred Term (AET02) 
Protocol: GB41149 
Analysis Population:  
(1) Placebo Run-in Period; Run-in safety-evaluable population (PERIOD1_PEFL) 
(2) 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-evaluable 
population (PERIOD2_SE) 












Parameter: <parameter> 
Visit 
 
 
Placebo 
(N = XXX) 
MTPS9579A Active 
(N = XXX) 
All Patients 
(N = XXX) 
Baseline 
Value at Visit 
n 
XXX 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
Day 22 
Value at Visit 
n 
XXX 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
 
Change from 
Baseline 
n 
XXX 
XXX 
XXX 
 
 
Mean (SD) 
XXXX (XXX) 
XXXX (XXX) 
XXXX (XXX) 
 
 
Median 
XXXX 
XXXX 
XXXX 
 
 
Min - Max 
XXX - XXXX 
XXX - XXXX 
XXX - XXXX 
 
 
 
 
 
 
 
Percent 
Change from 
Baseline 
n 
XXX 
XXX 
XXX 
 
 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Median 
XX.X (XX.X) 
XX.X (XX.X) 
XX.X (XX.X) 
 
 
Min - Max 
XX.X (XX.X) 
XX.X (XX.X) 
XX.X (XX.X) 
… 
 
 
 
 
 
 
Output 4.18 Laboratory Test Results with Highest WHO Grade Post-
Baseline (LBT07) 
Protocol: GB41149 
Analysis Population: Double-Blind Treatment Period; Safety-evaluable population (PHASE2_SE) 
 












Preferrered Name 1 
Investigator Text 1  
Preferrered Name 2 
Investigator Text 1  
 
Output 4.29 Listing of Deaths (AEL04) 
Protocol: GB41149 
Analysis Population: Safety-evaluable population 
 
Treatment: PLACEBO 
 
Center/ 
Patient ID 
Age/Sex/Race 
 
Date of First Study 
Drug 
Administration 
Day of Last Study 
Drug 
Administration 
Day of Death 
Cause of Death 
Autopsy 
Performed? 
 
/F/
 
 
12 
62 
Myocardial 
infarction 
Yes 
 
/M/
 
 
  
36 
37 
Ischemic Stroke 
No 
 
 
Output 4.30 Listing of Pregnancy Results 
Protocol: GB41149 
Analysis Population: Safety-evaluable population 
 
Treatment: PLACEBO 
_______________________________________________________________________________________________________________________________ 
Center/Patient ID     Age/Sex/Race  Type of Sample  Visit  
         Date of Collection  
Pregnancy Result Result  Unit 
_______________________________________________________________________________________________________________________________ 
 
   
/F/
 
 Blood   
SCREENING 
:08:40:00             <0.6  
             mU/mL 
Blood  
 
SCREENING 
:08:40:00             NEGATIV 
… 
______________________________________________________________________________________________________________________________ 
 
Output 4.31 Glossary of Adverse Event Preferred Terms and Investigator-
Specified Adverse Event Terms (AEL01_NOLLT) 
Protocol: GB41149 




Output 4.32 Listing of Adverse Events (AEL02_ED) 
Protocol: GB41149 
Analysis Population: 
(1) Placebo Run-in Period; Run-in safety-evaluable population (PERIOD1_PEFL) 
(2) 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-evaluable 
population (PERIOD2_SE) 
(3) 3 patients that were administered saline by IV infusion without IP at week18 visit (DEVI) 
 
Treatment: <Treatment> 
  
Center/Patient ID 
Adverse Event 
MedDRA 
Preferred Term 
Age/Sex/Race 
 
 
 
Study Day 
at Onset 
Time from 
Last Dose 
to Onset 
days hrs mins 
AE 
Duration 
in Days 
Serious 
Most 
Extreme 
Intensity 
Cause
d by 
Study 
Drug 
Outcome 
(1) 
Treatment 
for AE 
Action 
Taken 
(2) 
 
/F/
 
  
  
  
  
  
  
  
  
  
ANEAMIA NOS 
  
 xxx* 
xxx  xx   xx 
  1** 
No 
Mild 
Yes 
2 
No 
2 
   APPETITE DECREASED 
xxx 
xxx  xx   xx 
2 
No 
Moderate 
No 
3 
No 
3 
 
/M/
 
  
  
  
  
  
  
  
  
  
 DIARRHEA NOS 
  
xxx 
xxx  xx   xx 
  2** 
No 
Mild 
No 
3 
No 
2 
  
(1) Outcome: 1 = fatal; 2 = not recovered/not resolved; 3 = recovered/resolved; 4 = recovered/resolved with sequelae; 5 = 
recovering/resolving; 6 = unknown. 
(2) Action taken: 1 = dose increased; 2 = dose not changed; 3 = dose reduced; 4 = drug interrupted; 5 = drug withdrawn; 6 = not 
applicable; 7 = unknown. 
  
*  Study day derived from imputed onset date 
** Duration derived from imputed onset date and/or end date 
 
Output 4.33 Listing of Serious Adverse Events (AEL03) 
Protocol: GB41149 
Analysis Population:  
(1) Placebo Run-in Period; Run-in safety-evaluable population (PERIOD1_PEFL) 
(2) 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-evaluable 
population (PERIOD2_SE) 
 
Treatment: PLACEBO 


Center/Patient ID 
SAE MedDRA 
Preferred Term 
Age/Sex/Race 
 
 
 
Date of First 
Study Drug 
Administratio
n 
Study Day 
of Onset 
AE 
Duration in 
Days 
Most 
Extreme 
Intensity 
Caused 
by 
Study 
Drug 
Outcom
e 
(1) 
Treatment 
for SAE 
Action 
Taken 
(2) 
  
  
Reason 
Classified 
as Serious 
(3) 
 
/F/
 
  
  
  
  
  
  
  
  
  
ANEAMIA NOS 
  
 
60* 
1** 
Mild 
Yes 
2 
No 
2 
2 
   APPETITE DECREASED 
 
91 
2** 
Moderate 
No 
3 
No 
3 
3 
 
/M
 
  
  
  
  
  
  
  
  
  
 DIARRHEA NOS 
  
 
425 
2 
Mild 
No 
3 
No 
2 
6 
(1) Outcome: 1 = fatal; 2 = not recovered/not resolved; 3 = recovered/resolved; 4 = recovered/resolved with sequelae; 5 = 
recovering/resolving; 6 = unknown. 
(2) Action taken: 1 = dose increased; 2 = dose not changed; 3 = dose reduced; 4 = drug interrupted; 5 = drug withdrawn; 6 = not 
applicable; 7 = unknown <; Withdrawal = withdrawal from study>. 
(3) Reason classified as serious: 1 = resulted in death; 2 = life threatening; 3 = required or prolonged in patient hospitalization; 4 = 
disabling; 5 = a congenital anomaly/birth defect in offspring of study subject; 6 = does not meet any of the above serious criteria, but 
may jeopardize the subject, and may require medical or surgical intervention to prevent one of the outcomes listed above 
  
*  Study day derived from imputed onset date 
** Duration derived from imputed onset date and/or end date 
 
 
Output 4.34 Listing of Adverse Events Leading to Study Treatment 
Discontinuation (AEL02_ED) 
Protocol: GB41149 
Analysis Population: 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-
evaluable population (PERIOD2_SE) 
 
[Similar to output 4.32] 
 
Output 4.35 Listing of Adverse Events Leading to Study Discontinuation 
(AEL02_ED) 
Protocol: GB41149 
Analysis Population: 48-Week Double-Blind Treatment Period and 12-Week Safety Follow-up Period; Safety-
evaluable population (PERIOD2_SE) 
 
[Similar to output 4.32] 


 
Output 4.36 Listing of Laboratory Abnormalities (including WHO grade) 
(LBL02A) 
Protocol: GB41149 
Analysis Population: Safety-evaluable population 
 
TREATMENT: <Treatment> 
Lab Test 
(Unit) 
Center / 
Patient ID 
Study 
Day 
Cycle 
Date 
Days 
Since 
Last Dose 
of Study 
Drug 
Result 
 
Lab 
Normal 
Range 
WHO 
Grade 
<Lab Test> 
(<unit>) 
xxxx/xxx 
xx 
xx 
ddMMMYY 
xx 
xx 
 
 
xx-xx 
xx 
  
xxxx/xxx 
xx 
xx 
ddMMMYY 
xx 
xx 
xx-xx 
xx 
  
xxxx/xxx 
xx 
xx 
ddMMMYY 
xx 
xx 
xx-xx 
xx 
  
xxxx/xxx 
xx 
xx 
ddMMMYY 
xx 
xx 
xx-xx 
xx 
  
xxxx/xxx 
xx 
xx 
ddMMMYY 
xx 
xx 
xx-xx 
xx 
  
xxxx/xxx 
xx 
xx 
ddMMMYY 
xx 
xx 
xx-xx 
xx 
  
  
  
  
  
  
  
  
  
 
Output 4.37 Listing of Vital Signs (VSL01) 
Protocol: GB41149 
Analysis Population: Safety-evaluable population 




Graphs 
Output 5.1 Mean Value of Active Tryptase Over Time in Nasosorption 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
 
Output 5.2 Mean Value of Total Tryptase Over Time in Nasosorption 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.3 Mean Value of Active Tryptase Over Time in Nasosorption - 
Urea Normalized 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.4 Mean Value of Total Tryptase Over Time in Nasosorption - Urea 
Normalized 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.5 Mean Value of Total Tryptase Over Time in Serum 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (SERUM_SE) 
Output 5.6 Mean Percent Change From Baseline of Total Tryptase Over 
Time in Serum 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (SERUM_SE) 
Output 5.7 Mean Percent Change From Baseline of Active Tryptase Over 
Time in Nasosorption 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.8 Mean Percent Change From Baseline of Total Tryptase Over 
Time in Nasosorption 
Protocol: GB41149 


Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.9 Mean Percent Change From Baseline of Active Tryptase Over 
Time in Nasosorption - Urea Normalized 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
 
Output 5.10 Mean Percent Change From Baseline of Total Tryptase Over 
Time in Nasosorption - Urea Normalized 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.11 Mean Value of Urea Over Time in Nasosorption 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (NASO_SE) 
Output 5.12 Mean Value of Urea Over Time in Serum 
Protocol: GB41149 
Analysis Population: Safety-evaluable population; Nasosorption results (SERUM_SE)