Asthma
Conditions
Keywords
Asthma, Bronchitis
Brief summary
The main objective of this study is to evaluate the safety and tolerability of multiple fixed doses of MEDI-528 in adult patients with stable asthma and exercise-induced bronchoconstriction (EIB).
Detailed description
The primary objective of this study is to evaluate the safety and tolerability of multiple fixed escalating SC doses of MEDI-528 in adult patients with stable asthma and exercise-induced bronchoconstriction (EIB).
Interventions
BIOLOGICALMEDI528 50 mg
MEDI-528 at a dose of 50 mg administered as a subcutaneous injection twice weekly for 4 weeks
OTHERPLACEBO
Placebo administered as a subcutaneous injection twice weekly for 4 weeks
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
Patients must meet all of the following criteria: * Male or female adults, age 18 through 50 years at the time of screening; * Weight 50-100 kg and body mass index ≤ 35; * Written informed consent obtained from the patient prior to receipt of any study medication or beginning study procedures; * Documented clinical history of asthma and receiving stable treatment for ≥ 1 month prior to Study Day 0; * Airway hyperresponsiveness (AHR) on methacholine inhalation challenge testing at screening (or a documented history within the past 6 months), with provoking concentration of methacholine to cause a 20% fall in FEV1(subscript) (PC20) ≤ 8 mg/mL (Crapo, 2000); * Exercise-induced bronchoconstriction (EIB) with a decrease in FEV1 (subscript) of ≥ 15% from pre-exercise challenge testing level at screening; * Able to provide spirometry readings that meet American Thoracic Society (ATS) and European Respiratory Society (ERS) standards (Miller, 2005); * Women of childbearing potential, unless surgically sterile or at least 1 year post-menopausal, must use two effective methods of avoiding pregnancy (including oral, transdermal, or implanted contraceptives, intrauterine device, female condom, spermicide, diaphragm, cervical cap, abstinence, contraceptive foam, or use of a condom by the sexual partner or sterile sexual partner) from screening through Study Day 0, and must agree to continue using such precautions through Study Day 150. Cessation of birth control after this point should be discussed with a responsible physician. Men, unless surgically sterile, must likewise use an effective method of birth control (condom with spermicide) and must agree to continue using such precautions from screening through Study Day 150; * Able to complete the study period, including follow-up period, of up to approximately 150 days; and * Willing to forego other forms of experimental treatment and study procedures during the study and for 30 days after the follow-up period is completed.
Exclusion criteria
Patients must have none of the following criteria: * Receipt of MEDI-528 in any previous clinical study; * History of allergy or reaction to any component of the study drug formulation; * Lung disease other than asthma (eg, chronic obstructive pulmonary disease, cystic fibrosis); * Forced expiratory volume in 1 second (FEV1-subscript) \< 70% of predicted values at screening; * Use of systemic immunosuppressive drugs including systemic corticosteroids, ICS with doses \> 800 μg/day budesonide (or another ICS of equivalent dose), long-acting β2 agonists, cromolyn sodium, nedocromil sodium, leukotriene receptor antagonists, theophylline, or omalizumab from screening through Study Day 150; * Current use of any β-adrenergic antagonist (eg, propranolol); * Any disease or illness, other than asthma, that is likely to require the use of systemic corticosteroids during the study period; * Acute illnesses or evidence of significant active infection, such as fever ≥ 38.0°C (100.5°F) from screening through Study Day 0; * Current allergy vaccination therapy (desensitization immunotherapy); * Receipt of any investigational drug therapy within 30 days or any biologic(s) within 5 half-lives of the agent prior to screening; * Pregnancy (women of child bearing potential, unless surgically sterile or at least 1 year postmenopausal, must have a negative serum and urine pregnancy test at screening before methacholine inhalation challenge testing and a negative urine pregnancy test prior to study drug administration on Study Day 0); * Breastfeeding or lactating woman; * Evidence of infection with hepatitis B or C virus or HIV-1 or HIV-2, or active infection with hepatitis A; must have negative HIV-1, HIV-2, hepatitis A, B, and C tests at screening; * History of cancer other than basal cell carcinoma of the skin or cervical carcinoma-in-situ treated with apparent success with curative therapy more than 1 year prior to Study Day 0; * History of primary immunodeficiency * History of pancreatitis or currently active gastroduodenal ulcer; * Current use of tobacco products or a history of use of tobacco products of more than one cigarette per month or equivalent within 1 year prior to randomization or history of smoking of ≥ 10 pack-years; * History of life-long urinary retention; * History of anaphylaxis (defined as immediate life-threatening event requiring medical invention); * Elective surgery planned from screening through Study Day 150; * Clinically significant abnormality, as determined by the investigator, on 12-lead ECG or chest radiograph at screening; * History of any disease, evidence of any current disease (other than asthma), any finding upon physical examination, or any laboratory abnormality, that, in the opinion of the investigator or medical monitor, may compromise the safety of the patient in the study or confound the analysis of the study; or * Any employee of the research site who is involved with the conduct of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | Days 0 - 150 | Number of participants experiencing adverse events (includes both adverse events and serious adverse events) |
| Incidence of Serious Adverse Events | Days 0 - 150 | Number of participants experiencing serious adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise) | The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the percent maximum change in FEV1 before and after exercise on Day 28. |
| Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise) | AUC of FEV1 at Day 28 |
| Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise) | Time to return in minutes to 90 percent of baseline FEV1 (prior to exercise) after 30 minues of exercise on Day 28 |
| Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | Days 0, 28, 56, 119, and 150 | Number of participants with ADA to MEDI-528 |
| Mean Trough Concentration at Last Measurable Time Point (Cmin_last) | Days 0, 3, 7, 10, 14, 17, 21, 24, 28, 32, 37, 42, 56, 70, 84, 119, and 150 | Cmin\_last of MEDI-528 |
| Half-life (T1/2) | Days 0, 3, 7, 10, 14, 17, 21, 24, 28, 32, 37, 42, 56, 70, 84, 119, and 150 | T1/2 of MEDI-528 |
| Accumulation Index | Days 0 and 24 | Ratio of trough concentrations after first (Day 0) and last (Day 24) dose of MEDI-528 |
| Mean Trough Concentration (Cmin) | Days 0, 3, 7, 10, 14, 17, 21, 24, 28, 32, 37, 42, 56, 70, 84, 119, and 150 | Cmin of MEDI-528 |
| Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise) | The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the maximum change in FEV1 measured before and after exercising on Day 28. |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 11 subjects participated in this study from 26Feb2008 to 27Dec2008 at 4 sites in the United States of America.
Pre-assignment details
Treatment assignments were determined using a block randomization procedure with a 2:1 ratio (MEDI-528:placebo) via an interactive voice response system on Day 0 before study drug administration.
Participants by arm
| Arm | Count |
|---|---|
| PLACEBO Placebo administered as a subcutaneous injection twice weekly for 4 weeks | 4 |
| MEDI528 50 mg MEDI528 at a dose of 50 mg administered as a subcutaneous injection twice weekly for 4 weeks | 7 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | PLACEBO | MEDI528 50 mg | Total |
|---|---|---|---|
| Age, Continuous | 31.8 Years STANDARD_DEVIATION 13.5 | 32.1 Years STANDARD_DEVIATION 8.2 | 32.0 Years STANDARD_DEVIATION 9.7 |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 5 / 7 |
| serious Total, serious adverse events | 0 / 4 | 1 / 7 |
Outcome results
Primary
Incidence of Adverse Events
Number of participants experiencing adverse events (includes both adverse events and serious adverse events)
Time frame: Days 0 - 150
Population: All participants who received at least one dose of investigational product (MEDI-528 or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Incidence of Adverse Events | 4 Participants |
| MEDI528 50 mg | Incidence of Adverse Events | 6 Participants |
Primary
Incidence of Serious Adverse Events
Number of participants experiencing serious adverse events
Time frame: Days 0 - 150
Population: All participants who received at least one dose of investigational product (MEDI-528 or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO | Incidence of Serious Adverse Events | 0 Participants |
| MEDI528 50 mg | Incidence of Serious Adverse Events | 1 Participants |
Secondary
Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1)
The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the maximum change in FEV1 before and after exercise on Day 150.
Time frame: Day 150 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -0.54 Liter | Standard Deviation 0.62 |
| MEDI528 50 mg | Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -0.13 Liter | Standard Deviation 0.11 |
p-value: 0.53Two-sample t-test
Secondary
Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1)
The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the maximum change in FEV1 measured before and after exercising on Day 28.
Time frame: Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and performed acceptable spirometry (n=9, with 2 placebo and 7 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -0.43 Liter | Standard Deviation 0.23 |
| MEDI528 50 mg | Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -0.21 Liter | Standard Deviation 0.39 |
p-value: 0.4Two-sample t-test
Secondary
Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1)
The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the maximum change in FEV1 before and after exercise on Day 56.
Time frame: Day 56 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -0.60 Liter | Standard Deviation 0.04 |
| MEDI528 50 mg | Absolute Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -0.02 Liter | Standard Deviation 0.06 |
p-value: <0.01Two-sample t-test
Secondary
Accumulation Index
Ratio of trough concentrations after first (Day 0) and last (Day 24) dose of MEDI-528
Time frame: Days 0 and 24
Population: All participants who received at least one dose of MEDI-528 (n=7) and had available data (n=5).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 50 mg | Accumulation Index | 7.615 Ratio | Standard Deviation 5.215 |
Secondary
Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1)
AUC of FEV1 at Day 28
Time frame: Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | 92.69 Liter x min | Standard Deviation 41.14 |
| MEDI528 50 mg | Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | 86.04 Liter x min | Standard Deviation 15.62 |
Secondary
Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1)
AUC of FEV1 at Day 56
Time frame: Day 56 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=7, 2 placebo and 5 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | 85.38 Liter x min | Standard Deviation 44.72 |
| MEDI528 50 mg | Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | 83.35 Liter x min | Standard Deviation 22.66 |
Secondary
Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1)
AUC of FEV1 at Day 150
Time frame: Day 150 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=7, 2 placebo and 5 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | 82.53 Liter x min | Standard Deviation 18.31 |
| MEDI528 50 mg | Area Under the Curve (AUC) of Forced Expiratory Volume in 1 Second (FEV1) | 81.37 Liter x min | Standard Deviation 19.93 |
Secondary
Half-life (T1/2)
T1/2 of MEDI-528
Time frame: Days 0, 3, 7, 10, 14, 17, 21, 24, 28, 32, 37, 42, 56, 70, 84, 119, and 150
Population: All participants who received at least one dose of MEDI-528.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 50 mg | Half-life (T1/2) | 34.708 Day | Standard Deviation 7.891 |
Secondary
Incidence of Anti-drug Antibodies (ADA) to MEDI-528
Number of participants with ADA to MEDI-528
Time frame: Days 0, 28, 56, 119, and 150
Population: All participants who received at least one dose of MEDI-528.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MEDI528 50 mg | Incidence of Anti-drug Antibodies (ADA) to MEDI-528 | 0 Participants |
Secondary
Mean Trough Concentration at Last Measurable Time Point (Cmin_last)
Cmin\_last of MEDI-528
Time frame: Days 0, 3, 7, 10, 14, 17, 21, 24, 28, 32, 37, 42, 56, 70, 84, 119, and 150
Population: All participants who received at least one dose of MEDI-528.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 50 mg | Mean Trough Concentration at Last Measurable Time Point (Cmin_last) | 18.123 Microgram per milliliter | Standard Deviation 10.456 |
Secondary
Mean Trough Concentration (Cmin)
Cmin of MEDI-528
Time frame: Days 0, 3, 7, 10, 14, 17, 21, 24, 28, 32, 37, 42, 56, 70, 84, 119, and 150
Population: All participants who received at least one dose of MEDI-528.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MEDI528 50 mg | Mean Trough Concentration (Cmin) | 2.207 Microgram per milliliter | Standard Deviation 1.694 |
Secondary
Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1)
The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the percent maximum change in FEV1 before and after exercise on Day 28.
Time frame: Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and performed acceptable spirometry (n=9, 2 placebo and 7 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -12.6 Percent change | Standard Deviation 1.53 |
| MEDI528 50 mg | Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -6.49 Percent change | Standard Deviation 11.73 |
p-value: 0.22Two-sample t-test
Secondary
Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1)
The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the percent maximum change in FEV1 before and after exercise on Day 56.
Time frame: Day 56 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -20.1 Percent change | Standard Deviation 7.41 |
| MEDI528 50 mg | Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -1.01 Percent change | Standard Deviation 2.22 |
p-value: 0.16Two-sample t-test
Secondary
Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1)
The clinical activity of MEDI-528 on exercise-induced bronchoconstriction was measured by exercise challenge testing expressed as the percent maximum change in FEV1 before and after exercise on Day 150.
Time frame: Day 150 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -15.2 Percent change | Standard Deviation 15.48 |
| MEDI528 50 mg | Percent Maximum Change in Forced Expiratory Volume in 1 Second (FEV1) | -5.04 Percent change | Standard Deviation 3.91 |
p-value: 0.52Two-sample t-test
Secondary
Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1)
Time to return in minutes to 90 percent of baseline FEV1 (prior to exercise) after exercise on Day 150
Time frame: Day 150 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | 7.50 Minutes | Standard Deviation 3.54 |
| MEDI528 50 mg | Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | 5.00 Minutes | Standard Deviation 0 |
Secondary
Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1)
Time to return in minutes to 90 percent of baseline FEV1 (prior to exercise) after exercise on Day 56
Time frame: Day 56 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=8, 2 placebo and 6 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | 10.00 Minutes | Standard Deviation 0 |
| MEDI528 50 mg | Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | 5.00 Minutes | Standard Deviation 0 |
Secondary
Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1)
Time to return in minutes to 90 percent of baseline FEV1 (prior to exercise) after 30 minues of exercise on Day 28
Time frame: Day 28 (15 minutes prior to exercise and 5, 10, 15, 20, and 30 minutes after exercise)
Population: All participants who received at least 4 doses of investigational product (MEDI-528 or placebo; n=10, 3 placebo and 7 MEDI-528) and had available data (n=9, 2 placebo and 7 MEDI-528).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO | Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | 10.00 Minutes | Standard Deviation 0 |
| MEDI528 50 mg | Time to Return in Minutes to 90 Percent of Baseline Forced Expiratory Volume in 1 Second (FEV1) | 5.71 Minutes | Standard Deviation 1.89 |