A Study to Test if TEV-53275 is Effective in Relieving Asthma

The weekly asthma control status (Yes or No) is the derived asthma control composite score based on the following criteria:

1. Two or more of the following criteria were fulfilled:

• ≤2 days with a daily asthma symptom score >1; - ≤2 days of albuterol/salbutamol used as rescue medication up to a maximum of 4 occasions per week (multiple occasions per day are counted as separate occasions); - morning FEV1 ≥80% predicted for each day (by handheld device) and 2. Both of the following criteria were fulfilled:
• no night-time awakenings due to asthma; - no use of asthma maintenance medications.

The asthma control status in each weekly analysis window was Yes if the conditions 1 and 2 above were met, No otherwise.

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by a handheld device. The post-baseline analysis window for over 12 weeks was from the first day of study drug up to Day 84. The post-baseline analysis window for over 16 weeks was from the first day of study drug up to Day 112. The daily average of the efficacy data with each weekly analysis window was calculated based on non-missing e-diary as follow: Summation of FEV1 during an analysis window/Number of days with nonmissing data in the analysis window. LS mean and SE was calculated using an MMRM.

The number of times asthma rescue medication (number of inhalations/puffs) was used was assessed (for example, by reviewing the electronic diary or if required due to missing data in the diary, by site tracking of the inhalation counter on the inhaler). Rescue medication included albuterol sulfate inhalation powder (albuterol eMDPI) or equivalent albuterol/salbutamol. The post-baseline analysis window for over 12 weeks was from the first day of study drug up to Day 84. The post-baseline analysis window for over 16 weeks was from the first day of study drug up to Day 112. The daily average of the efficacy data with each weekly analysis window was calculated based on non-missing e-diary as follow: Summation of rescue medication uses during an analysis window/Number of days with nonmissing data in the analysis window. LS mean and SE were calculated using Wilcoxon rank-sum test stratified on randomization stratification factors.

An asthma control day was defined as a day on which the participant used 0 puffs of inhaled short-acting β-adrenergic agonist (SABA), had no night-time awakenings, and experienced no asthma exacerbations. The post-baseline analysis window for over 12 weeks was from the first day of study drug up to Day 84. The post-baseline analysis window for over 16 weeks was from the first day of study drug up to Day 112. Percentage of asthma control days in each analysis window was calculated as follow: Summation of asthma control days in an analysis window/Number of days with nonmissing data in the analysis window * 100.

FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. LS mean and SE were calculated using an MMRM.

The percent of predicted FEV1 (the volume of air exhaled in the first second of a forced expiration) was measured by handheld device.

The FVC is the volume of air that can be forcibly blown out after full inspiration. FVC results in this study were presented as the forced expiratory flow at 25% to 75% of FVC.

The FVC is the volume of air that can be forcibly blown out after full inspiration. FVC results in this study were presented as the forced expiratory flow at 25% to 75% of FVC. The post-baseline analysis window for over 12 weeks was from the first day of study drug up to Day 84. The post-baseline analysis window for over 16 weeks was from the first day of study drug up to Day 112. The daily average of the efficacy data with each weekly analysis window was calculated based on non-missing e-diary as follow: Summation of FEF25-75 during an analysis window/Number of days with nonmissing data in the analysis window. LS mean and SE were calculated using an MMRM.

The time (days) to the first CAE was the interval from the randomization to the occurrence of the first CAE. A CAE was defined as worsening asthma requiring treatment with a systemic corticosteroid for at least 3 days, emergency room visit resulting in systemic corticosteroid treatment, or hospitalization due to asthma. Worsening asthma included new or increased symptoms or signs that either worried the participant or were related to an asthma-specific alert (if available through the electronic diary/handheld spirometer) and required the addition of maintenance medications (other than systemic corticosteroids) to control the participant's asthma symptoms based on the investigator's judgment.

The ACQ-6 is a validated 6-item asthma assessment tool that has been widely used. Six questions are self-assessments (completed by the participant), 5 questions assessing asthma symptoms: night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and 1 question for short-acting bronchodilator use. Each item on the ACQ has a possible score ranging from 0 (no impairment) to 6 (maximum impairment), and the total score is the mean of all responses. The total score ranging from 0 (totally controlled) to 6 (severely uncontrolled) with higher scores indicating maximum impairment.

The Asthma Control Test (ACT) is a participant self-administered tool for identifying those with poorly controlled asthma comprising 5 items, with 4-week recall (on symptoms and daily functioning). It assesses the frequency of shortness of breath and general asthma symptoms, the use of rescue medications, the effect of asthma on daily functioning, and the overall self-assessment of asthma control measured on a 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled). Total scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma.

The AQLQ[S] (participants ≥18 years of age version) was self-administered by participants. The questionnaire is a tool to measure the impact of asthma on a participant's quality of life (physical, emotional, social, and occupational). The aim of the questionnaire is to evaluate the problems that were most troublesome to participants in their day to day lives. The questionnaire contains 32 items with a 2-week recall period and used a 7-point Likert scale (7=not impaired at all to 1=severely impaired). The overall AQLQ score was the mean of the responses to each of the 32 questions and ranged from 1 (severely impaired) to 7 (not impaired at all) with higher scores indicating better quality of life.

FEV1 was the volume of air exhaled in the first second of a forced expiration. FVC is the volume of air that can be forcibly blown out after full inspiration.

An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse events (SAEs) were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs that occurred after the first dose of study drug was administered through the end of the study. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Concomitant asthma medications included Antihistamines for systemic use (Cetirizine); Corticosteroids for systemic use (Prednisone, Methylprednisolone); and Drugs for obstructive airway diseases (Salbutamol, Fluticasone etc.).

A participant was classified as having a treatment-emergent ADA response if either of the following were true: - The participant had a positive sample at any of the postdose time points, but not at the predose (baseline) time point; - The participant had a positive sample at predose (baseline) and 1 or more postdose time points, but the titer of a postdose sample(s) was increased by at least 4-fold when comparing it to that of the predose sample.

Potentially clinically significant serum chemistry abnormalities included: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase, Gamma-glutamyl transpeptidase (GGT), Lactate dehydrogenase (LDH), and Creatinine phosphokinase each ≥3 * upper limit of normal (ULN); Blood urea nitrogen ≥10.71 millimoles (mmol)/liter (L); Creatinine ≥177 micromoles (μmol)/L; and Bilirubin (total) ≥34.2 μmol /L.

Potentially clinically significant hematological abnormalities included: White blood cells (WBCs) count ≤3.0 *10^9 cells/L or ≥20 * 10^9 cells/L; Hemoglobin ≤95 grams (g)/L in females and ≤115 g/L in males; Hematocrit <0.32 L/L in females and <0.37 L/L in males; Platelet count ≤75 * 10^9 cells/L or ≥700 * 10^9 cells/L; and Absolute neutrophil count (ANC) ≤1 * 10^9 cells/L.

Potentially clinically significant urinalysis abnormalities included: ≥2 unit increase from baseline in urine hemoglobin, ketones, glucose, and total protein.

Potentially clinically significant vital signs abnormalities included: Systolic blood pressure (BP): ≤90 millimeters of mercury (mmHg) and decrease from baseline of 20 mm Hg or ≥180 mm Hg and increase from baseline of ≥20 mm Hg; Diastolic BP: ≥105 mmHg and increase from baseline of ≥15 mmHg or ≤50 mmHg and decrease from baseline of ≥15 mmHg; Pulse ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm or ≤50 bpm and decrease from baseline of ≥15 bpm; Temperature ≥38.3 degrees celsius (ºC) and change from baseline of ≥1.1 ºC; Respiratory rate >24 breaths/min and increase from baseline of ≥10 breaths/min.

Potentially clinically significant electrocardiogram abnormalities including any one of the following values: QTc interval >450 milliseconds (msec) and QTc interval increases from baseline >30 msec, QTc interval >450 msec and QTc interval increases from baseline >60 msec, QTc interval >500 msec and QTc interval increases from baseline >30 msec, QTc interval >500 msec and QTc interval increases from baseline >60 msec; QRS duration >110 msec and a 25% increase from baseline; and PR interval >200 msec and a 25% increase from baseline.

Injection site reactions included erythema, ecchymosis, induration, tenderness, warmth, and swelling. Number of participants with erythema, ecchymosis, and induration were reported in following categories: Absent; 5 millimeters (mm) to ≤50 mm (mild); >50 mm to ≤100 mm (moderate); and >100 mm (severe). Number of participants with tenderness, warmth, and swelling were reported in following categories: Absent; mild; moderate; and severe.

An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Number of participants who did not complete the study due to AEs were reported.