E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
T2-low/non-T2 Severe Uncontrolled Asthma |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the effect of TEV-48574 compared with placebo on loss of asthma control (LoAC) in adult patients with T2-low and non-T2 severe asthma uncontrolled on inhaled corticosteroids plus long-acting beta-agonists (ICS+LABA). |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objective is to evaluate the effect of TEV-48574 compared with placebo on a range of clinical measures of asthma control. Other objectives include the evaluation of the safety and tolerability, device-related events, pharmacokinetics, and immunogenicity of TEV-48574. Potential exploratory biomarker objectives may include characterization of TEV-48574 responders and support of development of scalable tools to identify likely responders in future studies.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. The patient is a man or woman of any ethnic origin, at least 18 years of age at the time of signature of the informed consent form (ICF). b. The patient has a diagnosis of asthma for at least 12 months prior to the initial screening visit. f. The patient has demonstrated ≥12% response to a bronchodilator from baseline FEV1 within 30 minutes after 4 inhalations of albuterol/salbutamol HFA MDI (90 mcg ex actuator) or equivalent (eg, Ventolin) at screening. g. The patient has asthma with a FEV1 ≥40% and <80% of the value predicted for age, height, sex, and race at screening. For further inclusion criteria, see protocol. |
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E.4 | Principal exclusion criteria |
a. The patient has any other pulmonary diagnosis that in the opinion of the investigator and/or the clinical study physician could adversely affect patient safety or interpretation of study results. Examples include but are not limited to: chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, cystic fibrosis, bronchopulmonary dysplasia, and interstitial lung disease (including eosinophilic granulomatosis with polyangiitis [EGPA] which is expressly prohibited). b. The patient has any concomitant conditions or treatments that could interfere with study conduct, influence the interpretation of study observations/results, or put the patient at increased risk during the study as judged by the investigator and/or the clinical study physician. c. The patient has any of the following medical conditions: - Conditions that may mimic asthma (eg, vocal cord dysfunction, hyperventilation, panic attacks, cardiac asthma, uncontrolled gastroesophageal reflux disease [gastroesophageal reflux disease controlled on a stable proton pump inhibitor regimen for at least 1 month may be allowed]) - Conditions of immunodeficiency, immunocompromise, and/or conditions requiring immunomodulatory therapy - A history of malignancy within 5 years before screening (exception: basal cell carcinoma or in situ carcinoma of the cervix if successful curative therapy occurred at least 12 months prior to screening) - Tested positive for tuberculosis (TB) at screening by the QuantiFERON® TB Gold Test, or had a history of latent or active TB - Known history of, or a positive test result for, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) types 1 or 2 at screening - A history of more than one herpes zoster episode or multimetameric herpes zoster - A history of an opportunistic infection (eg, cytomegalovirus retinitis, Pneumocystis carinii, aspergillosis, Clostridium difficile) - A history of or ongoing chronic or recurrent infectious disease (eg, infected indwelling prosthesis, osteomyelitis, chronic sinusitis) - A suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the initial screening visit. Note: Patients who develop an upper respiratory infection/lower respiratory infection (URI/LRI) during the screening period may rescreen 2 weeks after symptoms resolve subject to local or regional public health directives. - Patients with clinical symptoms that may indicate COVID-19 infection, and/or patients who in the investigator’s opinion were at high risk of exposure to COVID-19 within 6 weeks before screening or during screening/run-in, will be tested for active COVID-19 infection and will only be included if they test negative for COVID-19. For further exclusion criteria see protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of patients who experience loss of asthma control (LoAC) during the treatment period. LoAC is defined as any one of the following during the treatment period: • Morning peak expiratory flow (PEF) decrease ≥30% from baseline on 2 consecutive days or morning handheld forced expiratory volume in the first second (FEV1) decrease ≥20% from baseline on 2 consecutive days • Increase in short-acting beta agonist (SABA)/quick-relief medication ≥6 puffs over baseline use in 24 hours on 2 consecutive days • Increase in ICS dose ≥4x most recent dose • Systemic corticosteroid use • Asthma ER visit or hospitalization
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients who experience loss of asthma control (LoAC) during the 16 week treatment period |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints are as follows: • Time from randomization to LoAC during the treatment period • Asthma Control Questionnaire 6-question version (ACQ-6) at end-of-treatment (EOT) and throughout the study • FEV1 (% predicted, L) at EOT and throughout the study • Use of SABA quick relief medication at EOT and throughout the study The other efficacy endpoints are as follows: • Proportion of patients who have a clinical asthma exacerbation (CAE) during the treatment period CAE is defined as a worsening of asthma symptoms resulting in any of the following: - The use of systemic corticosteroids (oral or injectable) - An emergency department visit due to asthma treated with systemic corticosteroids - An inpatient hospitalization due to asthma. Note: CAEs are a subset of LoACs • Time from randomization to first CAE during the treatment period • Number of nighttime awakenings due to asthma during the treatment period • Percent decrease in ICS dose during the treatment period • Other lung function parameters as assessed by hand-held spirometry at end of treatment (EOT) and throughout the study • Fractional exhaled nitric oxide (FeNO) throughout the study The safety endpoints for this study are as follows: • Frequency of adverse events • Change from baseline in clinical laboratory test results (serum chemistry, hematology, and urinalysis) throughout the study • Change from baseline in vital signs throughout the study • Change from baseline in 12-lead electrocardiogram (ECG) findings throughout the study • Use of concomitant medication • Local tolerability • Number (%) of patients who did not complete the study due to adverse events The pharmacokinetic endpoints for this study are as follows: • Trough serum TEV-48574 concentrations throughout the study (sparse sampling) • Population pharmacokinetic analysis of pharmacokinetic data The immunogenicity endpoints for this study are as follows: • Assessment of treatment-emergent anti-drug-antibody (ADA) results and responses: change from baseline and throughout the study • Impact of the presence of ADAs on pharmacokinetics and clinical safety (if possible) • Assessment of neutralizing ADA in ADA positive patients throughout the study
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Czech Republic |
Germany |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |