A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MTPS9579A in Patients With Asthma Requiring Inhaled Corticosteroids and a Second Controller

Study Overview
=================
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.

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

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: MTPS9579A
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documented physician-diagnosed asthma for at least 12 months prior to screening Treatment with asthma controller therapy (daily ICS [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 Documented history of >= 2 asthma exacerbation within the 12 months prior to screening while on daily ICS maintenance therapy For women of childbearing potential: agreement to remain abstinent or use contraception For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm Exclusion Criteria: 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 unwilling to abstain from smoking and/or e-cigarette use from the time of consent through the completion of the study History or evidence of any clinically significant medical condition/disease 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 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 Pregnant or breastfeeding, or intending to become pregnant during the study or within 60 days after the final dose of MTPS9579A Positive for TB at screening

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MTPS9579A<br> | Drug: MTPS9579A<br>* MTPS9579A IV infusion will be administered at the randomization visit (Week 2), Week 6, and every 4 weeks through Week 46.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo matching MTPS9579A will be administered at the randomization visit (Week 2), Week 6, and every 4 weeks thereafter through Week 46.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Composite Asthma Exacerbations (CompEX) Event | CompEX is defined as time from randomization to first asthma exacerbation or diary worsening during the treatment period. Asthma exacerbation was defined as new or increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that resulted in one or both of the following: Hospitalization or emergency department visit with administration of systemic corticosteroid treatment; Treatment with systemic corticosteroids for at least 3 days, or a long-acting depot corticosteroid preparation with a therapeutic effectiveness of at least 3 days. Diary worsening is based on the occurrence of prespecified changes in 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. Hazard ratio was used for the analysis. | Randomization [Week 2] to end of treatment (EOT) [Week 50] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Asthma Exacerbations | The number of asthma exacerbations per year was reported for this outcome measure. Asthma exacerbation was defined as new or increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that resulted in one or both of the following: Hospitalization or emergency department visit with administration of systemic corticosteroid treatment; Treatment with systemic corticosteroids for at least 3 days, or a long-acting depot corticosteroid preparation with a therapeutic effectiveness of at least 3 days. Poisson regression was used for the analysis. | Randomization [Week 2] to Week 50 | 
| Time to First Asthma Exacerbation | The time from randomization to first asthma exacerbation was measured. Asthma exacerbation was defined as new or increased asthma symptoms (wheezing, coughing, dyspnea, chest tightness, and/or nighttime awakenings due to these symptoms) that resulted in one or both of the following: Hospitalization or emergency department visit with administration of systemic corticosteroid treatment; Treatment with systemic corticosteroids for at least 3 days, or a long-acting depot corticosteroid preparation with a therapeutic effectiveness of at least 3 days. Cox regression was used for the analysis. | Randomization [Week 2] to Week 50 | 
| Absolute Change From Randomization in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 50 | FEV1 is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. 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/microliter (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. | Randomization [Week 2] to Week 50 | 
| Relative Percent Change From Randomization in Pre-Bronchodilator FEV1 at Week 50 | FEV1 was the volume of air exhaled in the first second of a forced exhalation as measured by spirometer. Measurements were performed before use of bronchodilator. Estimates are based on a mixed model for repeated measures (MMRM) analysis with an unstructured covariance matrix. The model used the relative 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. Relative change (%) in FEV1 = (absolute change in FEV1 / baseline FEV1) x 100. | Randomization [Week 2] to Week 50 | 
| Absolute Change From Randomization in Fractional Exhaled Nitric Oxide (FeNO) at Week 50 | FeNO is a volatile marker of airway inflammation that decreases with inhaled corticosteroid treatment. The measurements recorded were according to standardized procedures by the American Thoracic Society. 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. | Randomization [Week 2] to Week 50 | 
| Relative Percent Change From Randomization in FeNO at Week 50 | FeNO is a volatile marker of airway inflammation that decreases with inhaled corticosteroid treatment. The measurements recorded were according to standardized procedures by the American Thoracic Society. Relative change (%) in FeNO = (absolute change in FeNO / baseline FeNO) x 100. 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. | Randomization [Week 2] to Week 50 | 
| Percentage of Participants With Adverse Events | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. | Up to approximately Week 58 | 
| Area Under Concentration-Time Curve for the First Dosing Interval (AUClast) of MTPS9579A |  | Randomization [Week 2] to Week 6 | 
| Maximum Serum Concentration (Cmax) for the First Dosing Interval of MTPS9579A |  | 2-hour post-dose on Week 2 | 
| Steady State Cmax of MTPS9579A |  | 2-hour post-dose on Week 14 | 
| Maximum Time to Serum Concentration (Tmax) of MTPS9579A |  | Pre-dose and 2-hour post-dose on Week 2 | 
| Trough Serum Concentration (Ctrough) Accumulation Ratio of MTPS9579A | The accumulation ratio is calculated by taking the individual ratio of the Ctrough at Week 14 to the Ctrough at Week 6. | Predose on Weeks 6 and 14 | 
| Steady State Ctrough of MTPS9579A |  | Pre-dose on Week 14 | 
| Percentage of Participants With Anti-Drug Antibodies (ADA) to MTPS9579A | Treatment Emergent ADA is (a) negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result, OR (b) positive ADA result at baseline and one or more post-baseline titer results that are at least 0.60 titer unit (t.u.) greater than the baseline titer result. | Pre-dose Week 54 |