Asthma
Conditions
Brief summary
To evaluate the effect of MEDI-528 in adults with atopic asthma.
Detailed description
To evaluate the effect of MEDI-528 on the change in biologically active IL-9 levels in BAL fluid following segmental allergen challenge in adults with atopic asthma.
Interventions
OTHERPLACEBO
Placebo administered as a single intravenous infusion
BIOLOGICALMEDI528 9 mg/kg
MEDI-528 at a dose of 9 mg/kg administered as a single intravenous infusion
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Male or female adults, age 18 through 50 years of age at time of screening; * Written informed consent obtained from the patient prior to receipt of any study medication or beginning any study procedures; * Previously documented diagnosis of asthma based on episodic symptoms of airflow obstruction such as wheezing or chest tightness, with alternative diagnoses (eg, chronic obstructive pulmonary disease) ruled out; * Forced expiratory volume in one second (FEV1) ≥ 70% of predicted value; * A positive skin prick or intradermal test to cat allergen extract, short ragweed allergen extract, or dust mite allergen extracts. A positive skin test is defined as the indurations of skin test wheal being at least 2 mm greater in diameter than that of the indurations of the control skin wheal; * History of asthmatic symptoms upon exposure to at least one of the allergens (cat allergen extract, short ragweed allergen extract, or dust mite allergen extracts) that induces a positive skin prick test; * AHR on methacholine inhalation challenge test, with PC20 ≤ 8 mg/mL (Crapo, 2000); * No significant changes in regular asthma medications and no acute asthma exacerbations requiring oral corticosteroids or doubling of ICS dosage, hospitalization, emergency room visits, or unscheduled health care provider visits for asthma for at least 6 weeks prior to screening and up through the time of study drug administration; * No history of intubation or admission to an intensive care unit for asthma; * Sexually active women, unless surgically sterile or at least 1 year post-menopausal, must have used an effective method of avoiding pregnancy (including oral or implanted contraceptives, intrauterine device, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner) for 21 days prior to the study drug administration on Study Day 0, and must agree to continue using such precautions through Study Day 126. Cessation of birth control after this point should be discussed with a responsible physician. Sexually active men, unless surgically sterile, must likewise use an effective method of birth control (condom) and must agree to continue using such precautions through Study Day 126; * Able to follow study procedures including the ability to provide spirometry readings that meet American Thoracic Society (ATS)/European Respiratory Society (ERS) standards (Miller, 2005); * Ability to complete the study period, including follow-up period, of up to 126 days; and * Willing to forego other forms of experimental treatment and study procedures during study.
Exclusion criteria
* Receipt of MEDI-528 in any previous clinical study; * History of allergy or reaction to any component of the study drug formulation or other medications, such as topical lidocaine, administered during bronchoscopy; * Lung disease other than allergic asthma (eg, chronic bronchitis); * FEV1 \< 70% of predicted values; * Use of systemic immunosuppressive drugs including systemic corticosteroids (topical corticosteroids are permitted), ICS at doses \> 800 μg/day budesonide or equivalent, long-acting β2 agonists (eg, salmeterol), leukotriene antagonists, cromolyn sodium, nedocromil sodium, theophylline, omalizumab, or any other medication for asthma except short-acting β2 agonist (as needed) within the 4 weeks prior to screening up through administration of study drug; * Current use of any β-adrenergic antagonist (eg, propranolol); * Any disease or illness, other than asthma, that may require the use of systemic corticosteroids during the study period; * Upper or lower respiratory tract infections within 8 weeks before screening; * Acute illnesses or evidence of clinically significant active infection, such as fever ≥ 38.0°C (100.5°F) at screening and through the time of the study drug administration on Study Day 0; * Current allergy vaccination therapy (desensitization immunotherapy) with less than 3 months of stable maintenance doses prior to the baseline segmental allergen challenge. The allergy vaccination must not include desensitization to the allergen that will be used in the segmental allergen challenge; * Receipt of any investigational drug therapy within 30 days or any biologic(s) within 5 half-lives of the agent prior to study drug administration through Study Day 126; * Receipt of any therapy with a leukocyte-depleting agent (eg, rituximab, alemtuzumab) unless recovery in white cell count has been documented before screening; * Pregnancy (sexually active females must have negative serum and urine pregnancy tests at screening and a negative urine pregnancy test prior to study drug administration on Study Day 0); * Is a nursing mother at the time of screening; * Evidence of infection with hepatitis B or C virus, or HIV-1 or HIV-2, or active infection with hepatitis A; * History of significant systemic disease (eg, cancer, infection, hematological, renal, hepatic, coronary artery disease or other cardiovascular disease, endocrinologic, neurologic, rheumatologic, or gastrointestinal disease); * History of cancer other than basal cell carcinoma or cervical carcinoma-in-situ treated with apparently successful curative therapy (remission for ≥ 1 year prior to screening); * History of primary immunodeficiency; * History of pancreatitis or currently active gastroduodenal ulcer; * History of coagulation disorders or abnormal PT and PTT test results at screening; * History of life-long urinary retention; * History of use of tobacco products of more than one cigarette per month or equivalent within 1 year prior to screening or history of smoking of ≥ 10 pack-years; * History of anaphylaxis; * Elective surgery planned from the time of screening through Study Day 126; * Clinically significant abnormalities (other than asthma) upon physical examination prior to study drug administration on Study Day 0; * Clinically significant abnormality, as determined by the investigator, on 12-lead ECG or chest radiograph at the time of screening; * At the time of screening, any of the following: hemoglobin, total white blood cell count (WBC), platelet count, sodium (Na), potassium (K), chloride (Cl), or carbon dioxide (CO2)out of the normal range; aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), amylase, lipase, or serum creatinine above the upper limits of normal (ULN); or other abnormal laboratory values in the screening panel that are judged by the principal investigator to be clinically significant; or * No detectable levels of IL-9 in the Baseline Visit 2' BAL sample, or any finding upon physical examination or history of any disease that, in the opinion of the principal investigator or medical monitor, may compromise the safety of the patient in the study or confound the analysis of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Listing of Total Interleukin-9 (IL-9) Counts by Enzyme-linked Immunosorbent Assay in Bronchoalveolar Lavage Fluid (BAL) | Baseline (2 to 4 weeks prior to Day 0) and Day 15 | The response of biologically active IL-9 in BAL fluid to the segmental allergen challenge, 1-2 days after the applying the allergen, prior to and 2 weeks after investigational product administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Serious Adverse Events | Days 0 - 126 | Number of participants experiencing serious adverse events |
| Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | Days 0, 28, 56, 84, and 126 | Number of participants with ADA to MEDI-528 |
| Time to Peak Concentration (Tmax) | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | Tmax of MEDI-528 |
| Peak Concentration (Cmax) | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | Cmax of MEDI-528 |
| Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | AUC(0-t) of MEDI-528 |
| Incidence of Adverse Events | Days 0 - 126 | Number of participants experiencing adverse events (includes both adverse events and serious adverse events) |
| Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | AUC(ext) of MEDI-528 |
| Clearance (CL) | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | CL of MEDI-528 |
| Terminal Half-life (T1/2) | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | T1/2 of MEDI-528 |
| Volume at Steady State (Vss) | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | Vss of MEDI-528 |
| Volume at Distribution (Vz) | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | Vz of MEDI-528 |
| Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] | Days 0, 1, 7, 14, 15, 28, 56, 84, and 126 | AUC(0-infinity) of MEDI-528 |
Countries
United States
Participant flow
Recruitment details
A total of 11 adult participants participated in the study between 19Jul2007 and 15Oct2008 at 2 sites in the United States of America.
Pre-assignment details
Treatment assignments were determined using a block randomization procedure with a 1:1 ratio through an interactive voice response system. Only participants who had detectable levels of interleukin-9 in the Baseline Visit 2' bronchioalveolar lavage sample will be randomized.
Participants by arm
| Arm | Count |
|---|---|
| PLACEBO Placebo administered as a single intravenous dose | 5 |
| MEDI528 9 mg MEDI-528 at a dose of 9 mg/kg administered as a single intravenous infusion | 6 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | ABNORMAL LAB DATA AT SCREENING | 0 | 1 |
Baseline characteristics
| Characteristic | PLACEBO | MEDI528 9 mg | Total |
|---|---|---|---|
| Age, Continuous | 29.2 Years STANDARD_DEVIATION 7.8 | 22.3 Years STANDARD_DEVIATION 2.7 | 25.5 Years STANDARD_DEVIATION 6.4 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 5 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Listing of Total Interleukin-9 (IL-9) Counts by Enzyme-linked Immunosorbent Assay in Bronchoalveolar Lavage Fluid (BAL)
The response of biologically active IL-9 in BAL fluid to the segmental allergen challenge, 1-2 days after the applying the allergen, prior to and 2 weeks after investigational product administration.
Time frame: Baseline (2 to 4 weeks prior to Day 0) and Day 15
Population: All subjects who were randomized (n=11), received at least one dose of investigational product (MEDI-528 or placebo; n=10), and completed the 2-day BAL and segmental allergen challenge procedures at baseline (2-4 weeks prior to Day 0) and on Days 14 and 15 (n=2; 1 subject in each treatment group).
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| PLACEBO | Listing of Total Interleukin-9 (IL-9) Counts by Enzyme-linked Immunosorbent Assay in Bronchoalveolar Lavage Fluid (BAL) | Baseline | 8.31 Picograms per milliliter | 0 |
| PLACEBO | Listing of Total Interleukin-9 (IL-9) Counts by Enzyme-linked Immunosorbent Assay in Bronchoalveolar Lavage Fluid (BAL) | Day 15 | 40.05 Picograms per milliliter | — |
| MEDI528 9 mg/kg | Listing of Total Interleukin-9 (IL-9) Counts by Enzyme-linked Immunosorbent Assay in Bronchoalveolar Lavage Fluid (BAL) | Baseline | 4.04 Picograms per milliliter | 0 |
| MEDI528 9 mg/kg | Listing of Total Interleukin-9 (IL-9) Counts by Enzyme-linked Immunosorbent Assay in Bronchoalveolar Lavage Fluid (BAL) | Day 15 | 43.01 Picograms per milliliter | — |
Secondary
Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)]
AUC(0-infinity) of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Area Under the Concentration Curve From Time Zero to Infinity [AUC(0-infinity)] | 4845.344 Microgram times day per milliliter | Geometric Coefficient of Variation 17.8 |
Secondary
Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)]
AUC(0-t) of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Area Under the Concentration Curve From Time Zero to Last Measurable Concentration [AUC(0-t)] | 4347.489 Microgram times day per milliliter | Geometric Coefficient of Variation 24.1 |
Secondary
Clearance (CL)
CL of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Clearance (CL) | 167.702 Milliliters per day | Geometric Coefficient of Variation 2.7 |
Secondary
Incidence of Adverse Events
Number of participants experiencing adverse events (includes both adverse events and serious adverse events)
Time frame: Days 0 - 126
Population: All participants who were randomized (n=11) and received at least one dose of investigational product (MEDI-528 or placebo; n=10).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Incidence of Adverse Events | 5 Participants |
| MEDI528 9 mg/kg | Incidence of Adverse Events | 5 Participants |
Secondary
Incidence of Anti-drug Antibodies (ADA) to MEDI-528
Number of participants with ADA to MEDI-528
Time frame: Days 0, 28, 56, 84, and 126
Population: All participants who were randomized (n=11) and received at least one dose of investigational product (MEDI-528 or placebo; n=10). One subject in the 9 mg/kg group had no sample collected on Day 126.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
| MEDI528 9 mg/kg | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
Secondary
Incidence of Serious Adverse Events
Number of participants experiencing serious adverse events
Time frame: Days 0 - 126
Population: All participants who were randomized (n=11) and received at least one dose of investigational product (MEDI-528 or placebo; n=10).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Incidence of Serious Adverse Events | 0 Participants |
| MEDI528 9 mg/kg | Incidence of Serious Adverse Events | 0 Participants |
Secondary
Peak Concentration (Cmax)
Cmax of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Peak Concentration (Cmax) | 210.634 Microgram per milliliter | Geometric Coefficient of Variation 23.9 |
Secondary
Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)]
AUC(ext) of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Percent of Total Area Under the Concentration Curve Extrapolated From Last Measurable Time to Infinity [AUC(Ext)] | 8.283 Percentage of Total Area | Geometric Coefficient of Variation 78.8 |
Secondary
Terminal Half-life (T1/2)
T1/2 of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Terminal Half-life (T1/2) | 32.134 Day | Geometric Coefficient of Variation 3.6 |
Secondary
Time to Peak Concentration (Tmax)
Tmax of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Time to Peak Concentration (Tmax) | 0.040 Day | Geometric Coefficient of Variation 88.4 |
Secondary
Volume at Distribution (Vz)
Vz of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Volume at Distribution (Vz) | 7772.894 Milliliter | Geometric Coefficient of Variation 3.5 |
Secondary
Volume at Steady State (Vss)
Vss of MEDI-528
Time frame: Days 0, 1, 7, 14, 15, 28, 56, 84, and 126
Population: All participants who were randomized (n=11), received MEDI-528 (n=5), and had pharmacokinetic samples for analysis (n=4)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 9 mg/kg | Volume at Steady State (Vss) | 7354.025 Milliliter | Geometric Coefficient of Variation 5.6 |