Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Effects of MEDI-563, A Humanized Anti-Interleukin-5 Receptor Alpha Monoclonal Antibody, on Airway Eosinophils in Adults With Atopic Asthma
Brief Summary: Evaluate the safety and tolerability of MEDI-563 in adults with asthma and the effects of MEDI-563 on eosinophil counts in airway mucosal biopsies


Options:
A: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.
2. Female and male aged from 18 to 75 years, inclusively.
3. History of physician-diagnosed asthma requiring treatment with medium dose ICS and LABA.
4. Elevated level of peripheral blood eosinophil
5. Documented treatment with high-dose ICS and LABA for at least 6 months prior to Visit 1
6. Chronic oral corticosteroid therapy for at least 6 continuous months directly preceding Visit 1. Subjects must be on doses equivalent to 7.5 - 40 mg/day of prednisolone/prednisone at Visit 1 and be on a stable dose for at least 2 weeks prior to randomization. Patients must agree to switch to study required prednisone/prednisolone as their oral corticosteroid for the duration of the study.
7. Patients with documented failures of OCS reduction within 6 months prior to Visit 1 will not be required to proceed through the dose optimization phase during run-in.
8. Morning pre-bronchodilator (Pre-BD) FEV1 of \<80% predicted
9. Evidence of asthma as documented by either:

   Airway reversibility (FEV1 ≥12% and 200 mL) demonstrated at Visit 1, Visit 2, or Visit 3 using the Maximum Post-bronchodilator Procedure OR Documented reversibility in the previous 24 months prior to Visit 1 OR Airway hyperresponsiveness (PC20 FEV1 methacholine concentration ≤8mg/mL) documented in the previous 12 months prior to planned date of randomization OR Airflow variability in clinic FEV1 ≥20% between 2 consecutive clinic visits documented in the 12 months prior to the planned date of randomization (FEV1 recorded during an exacerbation should not be considered for this criterion).

   All patients must have reversibility testing performed before randomization to establish a baseline characteristic.

   If patients do not demonstrate airway reversibility at either Visit 1 or Visit 2 and this is needed to qualify the patient for randomization, the site should reiterate the need to withhold short- and long-acting bronchodilators prior to Visit 3 in an effort to meet this inclusion criterion.
10. At least 1 documented asthma exacerbation in the previous 12 months prior to the date informed consent is obtained
11. Optimized OCS dose reached at least 2 weeks prior to randomization
12. Additional asthma controller medication must not have been initiated during run in/optimization period (not applicable for management of exacerbations during screening/ run in optimization phase)
13. At least 70% compliance with OCS use
14. At least 70% compliance with usual asthma controller ICS-LABA
15. Minimum 70% (i.e. 10 of 14 days) compliance with asthma daily diary (morning and evening diary)

Exclusion criteria:

1. Clinically important pulmonary disease other than asthma or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

   * Affect the safety of the patient throughout the study
   * Influence the findings of the studies or their interpretations
   * Impede the patient's ability to complete the entire duration of study
3. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period
4. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during run-in/optimization period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study
5. History of life-threatening asthma
6. Asthma control reached at an OCS dose of ≤5mg during run-in/OCS optimization phase
7. Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS dose reduction criteria at Visit 5
8. Receipt of oral corticosteroids, other than prednisone or prednisolone, as the maintenance oral steroid controller for asthma symptoms from Visit 1 and throughout the study.
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the upper limit of normal (ULN) confirmed during screening period
B: Inclusion Criteria:

Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.

* Female and male aged 18 to 75 years, inclusively, at the time of Visit 1.
* Weight of ≥40 kg.
* Evidence of asthma as documented by post-bronchodilator (post-BD) reversibility in FEV1 of ≥ 12% demonstrated at Visit 2.
* Documented use of 1 of the following types of asthma therapy at time of informed consent: Low- to medium-dose ICS (ie, 100 to 500 μg fluticasone dry powder formulation equivalents total daily dose) with or without other controller medications, eg, an LTRA and/or theophylline or Low-dose ICS/LABA fixed combination therapy (eg, the lowest regular maintenance dose approved in the local country will meet this criterion)
* Morning pre-bronchodilator (pre-BD) FEV1 of \> 50% to ≤ 90% predicted at Visit 2.

Exclusion Criteria:

* Clinically important pulmonary disease other than asthma (eg, active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
* Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:
* Affect the safety of the patient throughout the study
* nfluence the findings of the studies or their interpretations,- Impede the patient's ability to complete the entire duration of study.
* Known history of allergy or reaction to the investigational product formulation.
* History of anaphylaxis to any biologic therapy.- History of Guillain-Barré syndrome.
* A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy.- Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period.
* Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study.
* Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll.
* A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
* History of cancer:
* Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.
* Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained
C: Inclusion criteria:

* Men aged 18 - 65 years inclusive, or women aged 18 - 50 years inclusive.
* Female subjects must be of non-childbearing potential,
* Male subjects must agree to abstain from sexual intercourse or use adequate contraception during sexual intercourse with pregnant or lactating females, in addition to their female partner using another form of contraception. This criterion must be followed from the time of the first dose of study medication until 84 days after the last dose of study medication.
* Body weight ≥ 50 kg and BMI within the range 19 - 29.9 kg/m2.
* Non-smoker as verified by urinary cotinine levels below 300 ng/mL at screening or ex-smokers who have given up smoking for \>12 months with a history \<10 pack years \[Pack yrs = (No of cigarettes/day x No of years smoked)/20\]
* Available to complete all study measurements.
* Able to read, comprehend, and write English at a sufficient level to complete study related materials.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Additional Inclusion Criteria for Subjects in Part I

• Healthy as determined by a responsible physician, based on a medical evaluation including history, physical examination, laboratory tests, cardiac monitoring.

Additional Inclusion Criteria for Subjects in Part II

* History of asthma for at least 6 months prior to the screening visit currently requiring no treatment or intermittent treatment with inhaled short-acting beta2-agonist only. Subject must not have received low dose inhaled corticosteroids within three months prior to Day 0.
* Pre-bronchodilator FEV1 \>70% but \<90% of predicted at screening with ≥12% reversibility after short-acting beta2-agonist or If the subject has a pre-bronchodilator FEV1 ≥90% at screening but has a history of asthma or if the subject meets the FEV1 criteria but does not demonstrate ≥12% reversibility after short-acting beta2-agonist administration, then the subject may be considered eligible if a Bronchial Provocation Test for asthma is positive (and after consultation with Medical Monitor and Principal Investigator). The bronchial provocation will be considered positive when the standard criteria for a positive response with the given challenge agent are met.
* Skin prick test positive for an allergen that is appropriate for nasal challenge

Exclusion criteria:

* As a result of medical interview, physical examination or screening investigations, the responsible physician deemed the subject unsuitable for the study.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation.
* Previous exposure to humanised antibody therapy for any reason.
* A strong family history of Th1 cytokine-related inflammatory disorders, including but not limited to, Type I diabetes mellitus, multiple sclerosis, Crohn's disease, rheumatoid arthritis, sarcoidosis.
* Known history of active or latent tuberculosis, or recent (within 6 months of study enrolment) exposure to a person with active tuberculosis. Previous medical history and letter from the subject's physician (GP) should exclude this.
* A history of chronic urogenital infections or other chronic infections.
* Subjects who have received any type of vaccination in the last two months.
* The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug(whichever is longer) prior to the first dose of current study medication
* Where participation in study would result in donation of blood in excess of 500 mL within a 56 day period
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John'sWort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.
* History of alcohol/drug abuse or dependence within 12 months of the study:
* Abuse of alcohol defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). 1 unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* A positive test for human immunodeficiency virus (HIV) antibodies.
* The subject has a positive pre-study urine drug/ urine alcohol screen. A minimum list of drugs that will be screened for include Amphetamines, Barbiturates, Cocaine, Opiates, Cannabinoids and Benzodiazepines.
* ECG that is outside of ranges as defined by the protocol
* Those who, in the opinion of the Investigator, have a risk of non-compliance with study procedures.
* The subject has a history of confirmed or active parasitic infection.
* The subject is unable to refrain from travelling to countries with a high prevalence of infectious (especially parasitic) disease from when the first dose is administered until the expected washout period is complete (plasma levels below LLQ) or the last follow-up visit, which ever is later
D: Inclusion Criteria:

* Male or female adults, 18 through 65 years of age at time of randomization;
* Written informed consent obtained from the subject prior to beginning study procedures or receipt of any study medication;
* Previously documented diagnosis of asthma of ≥ 1 year duration, based on episodic symptoms of airflow obstruction; post-bronchodilator reversibility of airflow obstruction ≥ 12% (in USA only - if subject does not achieve this during screening, proof of ≥12% reversibility within 1 year of randomization is acceptable) or proof of a positive response to a methacholine challenge during screening with prior approval from MedImmune (in USA only - within 1 year of randomization is acceptable) as represented by a provoking concentration of methacholine to cause a 20% fall in FEV1 (PC20) \< 8 mg/ml \[American Thoracic Society (ATS), 2000)\]; and exclusion of alternative pulmonary diagnoses (eg, cystic fibrosis, COPD);
* Asthma symptoms are adequately controlled on a therapeutic regimen that has not changed in the last 4 weeks prior to Study Day 0, and the subject is willing to maintain the same therapeutic regimen and doses from the time of screening to the time of the first follow-up bronchoscopy with airway mucosal biopsies (Study Day 28 for Cohort 1; Study Day 84 for Cohort 2);
* Pre-bronchodilator FEV1/forced vital capacity (FVC) ratio that is below the age-adjusted normal limit as defined by the 2007 National Heart Lung and Blood Institute Asthma guidelines (Appendix D) and post-bronchodilator FEV1 ≥ 65% at screening;
* Must have ≥ 2.5% eosinophils in sputum;
* Have had no hospitalizations due to asthma in the last year prior to screening;
* Women of childbearing potential, unless surgically sterile or at least 1 year post-menopausal, must use 2 effective methods of avoiding pregnancy
* Able to complete the follow-up period as required by the protocol;
* Willing to forego other forms of experimental treatment and study procedures during the study and during an 84-day period after the last dose of study drug;
* Able to provide spirometric readings that meet ATS standards

Exclusion Criteria:

* Participation in any previous MEDI-563 clinical study;
* Known history of allergy or adverse reactions to any component of the study drug formulation;
* Lung disease other than asthma (eg, COPD, cystic fibrosis, eosinophilic pneumonia);
* Current use of any systemic or inhaled immunosuppressive drugs \[oral (up to a maximum dose of 10 mg/day or 20 mg every other day) and inhaled corticosteroids are allowed if dose has been stable for at least 4 weeks prior to study drug administration on Study Day 0\].
* Current use of any β-blocker (eg, propranolol);
* Acute illnesses or evidence of clinically significant active infection, such as fever ≥ 38.0ºC (100.5ºF) at screening and through the time of the study drug administration on Study Day 0;
* Receipt of any investigational drug therapy, intravenous immunoglobulin (IVIG), or monoclonal therapy (eg, Xolair) within 30 days or within 5-half lives prior to study drug administration on Study Day 0 through End of Study/Study Termination (Study Day 84 for Cohort 1 or Study Day 140 for Cohort 2);
* Pregnancy (women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to study drug administration on Study Day 0);
* Breastfeeding or lactating;
* History of alcohol or drug abuse \< 1 year prior to Study Day 0;
* History of cancer, apart from basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy \> 1 year prior to Study Day 0;
* History of a previous episode of active TB or a positive TB skin test without completion of an appropriate course of treatment;
* A history of coagulation disorders that would contraindicate mucosal biopsies;
* History of immunodeficiency or infection with HIV-1, HIV-2, or hepatitis A, B, or C virus;
* History of use of tobacco products within 2 years of baseline (Study Day 0) or history of smoking ≥ 10 pack-years;
* Elective surgery planned from the time of screening through first follow-up bronchoscopy with airway mucosal biopsies (Study Day 28 or Study Day 84, as applicable);
* Evidence of any systemic disease or respiratory disease (other than asthma), history of any disease, or any finding upon physical examination, screening laboratory test, chest X-ray (CXR), or ECG that, in the opinion of the investigator or medical monitor, may compromise the safety of the subject in the study or confound the analysis of the study results;
* Any employee of the research site who is involved with the conduct of the study;
* History of lidocaine allergy

Answer: D