Clinical trial NCT02594332: Effects of Mepolizumab Compared to Placebo on Airway Physiology in Patients With Eosinophilic Asthma: MEMORY Study
Official title: A Randomized, Double-blind, Placebo-controlled, Mono-center Study to Evaluate the Effects of Mepolizumab on Airway Physiology in Patients With Eosinophilic Asthma: the MEMORY Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Asthma
Keywords: eosinophilic asthma
mepolizumab
treatment
Lead sponsor: Johannes Gutenberg University Mainz
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
First posted: 2015-11-03
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the MEMORY trial is to compare the effects of mepolizumab with Placebo on airway physiology in patients with eosinophilic asthma

Detailed description: Asthma with eosinophilic inflammation in the airways and/or blood eosinophilia is associated with clinical severity including the risk of exacerbations and relevant comorbidities (e.g. nasal polyposis). Interleukin-5 (IL-5) is a cytokine essential for eosinophil trafficking and survival. Clinical trials of blocking IL-5 with anti-IL-5 antibodies (mepolizumab and reslizumab) in patients with uncontrolled eosinophilic asthma resulted in an improvement in exacerbation rate and oral corticosteroid use. In some studies with mepolizumab and reslizumab there was a beneficial effect on lung function (FEV1). In addition, many patients described a profound impact on asthma symptoms and quality of life in personal reports which is not uniformly reflected in clinical trials.

The MEMORY trial is the first to primarily evaluate the effect of mepolizumab treatment on pulmonary function in patients with severe eosinophilic asthma. Importantly, using spirometry and bodyplethysmography will allow to evaluate additional parameters beyond FEV1 that more closely mirror the pathophysiological changes and functional aspects of airflow limitation in asthma in real life, e.g. airway resistance, hyperinflation and diffusion capacity. The proposed trial will answer the important questions: if, and if so, which parameters of airway (patho-) physiology as assessed by bodyplethysmography best reflect clinical response to mepolizumab therapy in patients with severe eosinophilic asthma. In addition, the time course to clinical response will be assessed. Equally important, there is only a loose correlation between FEV1 and parameters of asthma control and asthma-related quality of life. This is why another new and important aspect of this trial is to carefully monitor asthma control and asthma quality in life in correlation with lung function changes beyond FEV1. Finally, it is tempting to speculate that the proposed trial will contribute to the question how to best define clinical response to mepolizumab.

Eligibility criteria: Inclusion Criteria:

1. Patients must be able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form.
2. Male or female patients at least 18 years
3. Physician-diagnosis of asthma and evidence of asthma as documented by either reversibility of airflow obstruction (FEV1 ≥ 12% or 200 ml) demonstrated at visit 1 or visit 2 .
4. ICS dose must be ≥ 1000 μg/day BDP or equivalent daily with or without maintenance oral corticosteroids.
5. Treatment in the past 12 months with an additional controller medication for at least 3 successive months, e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline.
6. Persistent airflow obstruction as indicated by a pre-bronchodilator FEV1 \< 80% predicted recorded at Visit 1 or \< 90% for patients on oral corticosteroids.
7. An elevated peripheral blood eosinophil level of ≥ 300/µL that is related to asthma or ≥ 150/µL in patients treated with oral corticosteroids as maintenance therapy demonstrated at visit 1 or in the previous 12 months
8. Confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids (intramuscular, intravenous, or oral), in the 12 months prior to visit 1, despite the use of high-dose inhaled corticosteroids. For patients receiving maintenance corticosteroids, the corticosteroid treatment for the exacerbations must have been a two-fold increase or greater in the dose.

Exclusion Criteria:

1. Current smokers or former smokers with a smoking history of ≥ 10 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked). Patients who have not smoked for ≥ 6 months before visit 1 and have \< 10 pack years can be included into the study.
2. Presence of a clinically important lung condition other than asthma. This includes current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
3. Patients who have received omalizumab \[Xolair\] within 130 days of Visit 1.
4. Patients who have received any biological to treat inflammatory disease within 5 half-lives of visit 1

Primary outcomes:
measure: mean change from baseline in pre- and post-bronchodilator FVC at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
measure: mean change from baseline in pre- and post-bronchodilator FEV1 at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
measure: mean change from baseline in pre- and post-bronchodilator RV at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
measure: mean change from baseline in pre- and post-bronchodilator TLC at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
measure: mean change from baseline in pre- and post-bronchodilator airway resistance at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
measure: mean change from baseline in pre- and post-bronchodilator IC at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
measure: mean change from baseline in pre- and post-bronchodilator CO diffusion capacity at visit 10 (week 24) and at time of response
timeFrame: week 24 and time of response
Secondary outcomes:
measure: Mean change from baseline in pre- and post-bronchodilator forced vital capacity (FVC) over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second (FEV1) over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Mean change from baseline in pre- and post-bronchodilator residual volume (RV) over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Mean change from baseline in pre- and post-bronchodilator total lung capacity (TLC) over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Mean change from baseline in pre- and post-bronchodilator airway resistance over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Mean change from baseline in pre- and post-bronchodilator inspiratory capacity (IC) over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Mean change from baseline in pre- and post-bronchodilator CO diffusion capacity over the 48-week treatment period at prespecified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 months
measure: Exercise tolerance in a subgroup of patients: Mean change from baseline in exercise endurance time
timeFrame: 1, 3, 6, 9 and 12 month
measure: Exercise tolerance in a subgroup of patients: Mean change from baseline in inspiratory capacity (IC)
timeFrame: 1, 3, 6, 9 and 12 month
measure: Exercise tolerance in a subgroup of patients: Mean change from baseline in exertional dyspnea and leg discomfort (Borg CR10 Scale®)
timeFrame: 1, 3, 6, 9 and 12 month
measure: Time to clinical response and time to change of baseline parameters of clinical Response: sence of smell
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: sense of taste
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: lung volume
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: CO Diffusion capacity
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: FEV1 reversibility
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: exhaled NO (eNO)
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: blood eosinophils
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: eosinophilic cationic Protein (ECP)
timeFrame: 52 weeks
measure: Time to clinical response and time to change of baseline parameters of clinical Response: blood periostin
timeFrame: 52 weeks
measure: Mean change from baseline in Asthma Control Questionnaire (ACQ)
timeFrame: 52 weeks
measure: Mean change from baseline in Asthma Quality of Life Questionnaire (AQLQ)
timeFrame: 52 weeks
measure: Mean change from baseline in St. George´s Respiratory Questionnaire (SQRG)
timeFrame: 52 weeks
measure: Mean change from baseline in Dyspnoe Index (BDI/TDI)
timeFrame: 52 weeks
measure: Mean change from baseline in fatique
timeFrame: 52 weeks
measure: Mean change from baseline in number of days off school/work over the 48-week treatment period
timeFrame: 48 weeks
measure: Time to first clinically significant exacerbation requiring oral or systemic corticosteroids, hospitalization, and/or emergency department (ED) visits
timeFrame: 52 weeks
measure: Frequency of clinically significant exacerbations
timeFrame: 52 weeks
measure: Time to first exacerbation requiring hospitalization or emergency department (ED) visit
timeFrame: 52 weeks
measure: Frequency of exacerbations requiring hospitalization (including intubation and admittance to an intensive care unit (ICU)) or ED visits
timeFrame: 52 weeks
measure: GETE rating by physician and patient at time of response and over the 52-week treatment period at pre-specified timepoints (1, 3, 6, 9 and 12 months)
timeFrame: 1, 3, 6, 9 and 12 month
measure: Mean change in proportion of patients with nasal polyps, chronic sinusitis and loss of smell and taste
timeFrame: 52 weeks
measure: Clinical response to mepolizumab in relation to asthma parameters which potentially predict clinical response
timeFrame: 52 weeks
measure: Routine safety assessment (AE and SAE reporting, withdrawals, pregnancy, hematological and clinical chemistry parameters, ECG and vital signs (pulse rate and systolic and diastolic blood pressure))
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Pneumologie
Study officials:
affiliation: Johannes Gutenberg University Mainz
name: Stephanie Korn, MD
role: PRINCIPAL_INVESTIGATOR
References: