| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Asthma (an illness that causes breathing difficulty) that is not fully controlled, so that episodes of breathing difficulty are still occuring despite the use of other available treatments |
|
| 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 | 14.0 |
| 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 |
|
| 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 this study is to evaluate the effect of multiple-dose SC administration of MEDI-563 on the annual asthma exacerbation rate in adult subjects with uncontrolled, suspected eosinophilic asthma. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
1. To evaluate the safety and tolerability of MEDI-563.
2. To determine the optimal dose of MEDI-563 to be used in Phase 3 studies.
3. To describe the immunogenicity (IM) and pharmacokinetics (PK) of MEDI-563.
4. To assess the effect of MEDI-563 on other assessments of clinical activity (i.e. asthma control and pulmonary function).
5. To assess the effect of MEDI-563 on health-related quality of life. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 18 through 75 years at the time informed consent is obtained.
2. Written informed consent and any locally required authorization (eg, HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluatons.
3. Female subjects of childbearing potential who are sexually active with non-sterilized male partner must use adequate contraception from the date informed consent is obtained through the end of the study. An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. In this study, where medications and devices containing hormones are included, the recommended methods of contraception are described in Table 4.2.1-1 of the protocol. Sustained abstinence is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
4. Non-sterilized males who are sexually active with a female of child-bearing potential must use adequate contraception from the date informed consent is obtained through the end of the study.
5. Females or female partners not of childbearing potential must have been surgically sterilized (eg, hysteroctomy, bilateral tubal ligation, or bilateral oophorectomy) or postmenopausal (defined as at least 1 year since last regular menses) and follicle stimulating hormone (FSH) > 23 IU/L according to a central laboratory.
6. Sterilized males must be at least 1 year post vasectomy.
7. Weight of > 45 kg but equal to or less than 150 kg (>100 lb but equal to or less than 330 lb).
8. History of physician-diagnosed asthma for at least 12 months prior to the date informed consent is obtained.
9. Morning pre-bronchodilator forced expiratory volume in 1 second (FEV1) value of more than or equal to 40% and <90% predicted during the screening/run-in period.
10. Meeting any one of the following criteria: a) Proof of post-bronchodilator reversibility of airflow obstruction more than or equal to 12% documented within 36 months prior to randomization or proof of a positive response [PC20 less than or equal to 8 mg/mL (ATS, 2000)] to a methacholine challenge documented within 36 months prior to randomization; OR b) A post-bronchodilator increase in FEV1 greater than or equal to 12% and greater than or equal to 200ml at Week -3 screening visit: OR c) If a) and b) are not met and all other inclusion/exclusion criteria are met, subjects with a FEV1 of more than or equal to 1.5 L and more than or equal to 60% predicted on the Week -2 screening visit will be eligible to undergo a methacholine challenge at the Week -2 screening visit at sites where methacholine testing is available. If the subject achieves a positive response to this methacholine challenge (PC20 less than or equal to 8 mg/mL), then this inclusion criterion is met.
11. Physician prescribed daily use of medium-dose or high-dose ICS (as defined in GINA Report 2009) plus LABA or any combination of sequential dosing of either medium dose or high dose ICS/LABA for at least 12 months prior to the date informed consent is obtained. Dose must be stable for at least 30 days prior to the date informed consent is obtained and during the screening/run-in period.
12. Willingness to switch to an ICS/LABA combination product if using individual ICS and LABA inhalers prior to the date informed consent is obtained.
13. Dose of other asthma controller medications (leukotriene modifiers, theophylline, or cromones) must be stable for at least 30 days prior to the date informed consent is obtained).
14. At least 2, but not more than 6, documented asthma exacerbations in the 12 months prior to the date informed consent is obtained that required use of a systemic corticosteroid burst.
15. An Asthma Control Questionnaire (ACQ) score of more than or equal to 1.5 at least twice during the screening/run-in period .
16. For subjects 65 years of age or older, a chest x-ray (CXR) or chest computed tomography (CT) that is normal for an asthmatic population and excludes alternative diagnosis per the investigator during screening/run-in or within 12 months prior to the date informed consent is obtained.
17. Ability and willingness to complete the study to Week 66, and if needed to Week 92 for additional follow-up of peripheral blood eosinophil counts, as required by protocol. |
|
| E.4 | Principal exclusion criteria |
1. Any condition that, in the opinion of the investigator or medical monitor, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
2. Concurrent enrolment in another clinical study.
3. Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
4. Known history of allergy or reaction to any component of the investigational product formulation.
5. History of anaphylaxis to any biologic therapy.
6. Unexplained abdominal discomfort, nausea, vomiting, decreased appetite, and/or diarrhea within 30 days prior to the date informed consent is obtained & during the 3-week screening/run-in period; diagnosis of helminth parasitic infection resulting from positive stool sample during the 3-week screening/run-in period that has not been treated with, or has failed to respond to, standard of care therapy; or positive serology or stool sample for S stercoralis in subjects with chronic oral corticosteroid-dependent asthma during the 3-week screening/run-in period.
7. Use of immunosuppressive medication (eg methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent is obtained. Chronic oral prednisone or equivalent up to 10 mg daily or 20 mg every other day for asthma is allowed.
8. Oral corticosteroid burst or short-acting systemic corticosteroid within 30 days prior to the date informed consent is obtained or during the screening/run-in period.
9. Acute upper or lower respiratory infections requiring antibiotics or antiviral medications within 30 days prior to the the date informed consent is obtained or during the screening/run-in period.
10. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
11. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained. whichever is longer. Receipt of vaccinations (eg rubella, measles, chicken pox, vaccinations for travel abroad) is allowed providing administration was not within 3 weeks prior to any study visit.
12. Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
13. Previously received MEDI-563.
14. Any clinically relevant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening/run-in period, which in the opinion of the Investigator, may put the subject at risk because of his/her participation in study, or may influence the results of the study, or the subject's ability to participate in the study.
15. Past history of clinically significant cardiac disease or any ECG abnormality obtained during the screening/run-in period, which in the opinion of the Investigator may put the subject at risk or interfere with study assessments.
16. Breastfeeding or lactating women.
17. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained.
18. History of any known primary immunodeficiency disorder excluding asymptomatic selective IgA or IgG subclass deficiency.
19. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccinations without history of hepatitis B are allowed to enrol.
20. A positive HIV test or subject taking antiretroviral medications, as determined by medical history and/or subject's verbal report.
21. History of cigarette smoking more or equal to 10 pack-years or smoking within 12 months prior to the date informed consent is obtained.
22. Evidence of any systemic disease upon physical examination.
23. Known exposure to inhaled occupational agents or fumes with an established diagnosis of occupational asthma.
24. History of cancer, except for basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy more than 12 months prior to the date informed consent is obtained or other malignancies treated with apparent success with curative therapy more than 5 years prior to the date informed consent is obtained.
25. Planned surgical procedures during the conduct of the study.
26. Stable dose of allergy vaccinations regimen (immunotherapy) for less than 30 days prior to the date informed consent is obtained.
27. Subjects unable to demonstrate acceptable inhaler, peak flow meter, & spirometry techniques.
28. Current use of any oral or ophthalmic β-adrenergic antagonist (eg, propranolol). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of this study is to evaluate the effect of multiple-dose SC administration of MEDI-563 on the annual exacerbation rate in eosinophilic-positive adult subjects with uncontrolled asthma requiring medium-dose or high-dose ICS plus LABA and having a history of more than or equal to 2 but less than or equal to 6 documented asthma exacerbations in the 12 months prior to the date informed consent is obtained that required use of a systemic corticosteroid burst. The primary endpoint is the annual exacerbation rate during the study (Week 1 (Day 1) to Week 52) for eosinophilic-positive subjects only, where annual exacerbation rate is defined as the number of exacerbations from Week 1 (Day 1) to Week 52. If a subject discontinues before the Week 52 visit, the annual exacerbation rate for this subject will be calculated/observed Days x 364. The primary endpoint analysis will be conducted using the mITT Population at the 0.05 significant level without multiplicity adjustment this analysis will also be conducted on the PP population as a secondary analysis. The primary endpoint will be assessed by Cochran-Mantel-Haenszel (CMH) row mean score test (Van Elteren test) with baseline (Day 1) ICS use (approximately 60% of subjects on medium-dose vs. at leat 40% of subjects on high dose) as a stratification factor.
The comparison between the combined MEDI-563 groups (100 mg) from both eosinophilic-positive and eosinophilic-negative subjects versus combined placebo groups will be assessed as part of the exploratory analyses with baseline (Day 1) ICS use (approximately 60% of subjects on medium-dose vs. at least 40% subjects on high-dose) and eosinophilic phenotype (eosinophilic-positive vs. eosinophilic-negative) as stratification factors. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 1 [Day 1] to Week 52 |
|
| E.5.2 | Secondary end point(s) |
Safety and Tolerability: This will be assessed by summarizing AEs and SAEs using the safety population. The occurrence of AEs and SAEs will be described by system organ class (SOC), preferred term, severity, and relationship to the investigational product. Other variables used for the safety assessments include but not limited to ECG, vital signs, and routine laboratory assessments, which will be evaluated in the MEDI-563 and placebo groups as changes from baseline. These variables as well as their changes from baseline will be summarized descriptively. Neutrophil counts and CPK will be summarized separately with absolute value and change from baseline for each study visit. In addition, if warranted, shift tables will be included.
Dose Response: A dose-response model will be evaluated based on mITT population. The details of the dose-response analysis will be described in the statistical analysis plan.
Pharmacokinetics and Immunogenicity: MEDI-563 concentration data will be tabulated by treatment group together with descriptive statistics. Serum MEDI-563 concentration-time profiles by treatment group will be generated and included in the report. Population modeling will be performed to better characterize the PK of MEDI-563 given by SC injection in asthmatic subjects. The incidence rate of positive serum antibodies to MEDI-563 will be described by treatment group.
Asthma Control: Asthma control will be evaluated by ACQ, TNSS-3, and asthma symptom diary. The change from baseline in mean ACQ and TNSS-3 will be summarized by treatment and visit. The β2 agonist use and Asthma Symptom Diary will also be summarized weekly by treatment. Change from baseline in mean ACQ at various visits may be analyzed by ANCOVA with treatment and baseline values as possible covariates.
Pulmonary Function: Pulmonary function as measured by changes of airflow obstruction (FEV1 and FVC at the site and PEF and FEV1 at home) during the study will be assessed. The measurements, along with change from baseline at various time points will be summarized using descriptive statistics. ANCOVA with treatment arm and baseline value as possible covariates may be used to compare the changes from baseline in FEV1 and PEF between the individual MEDI 563 group and the placebo group, respectively.
Health-related Quality of Life: Health-related quality of life will be evaluated using the AQLQ(S) and EQ-5D. The overall score and the 4 domain scores from the AQLQ(S) responses, along with their respective changes from baseline will be summarized by treatment group and visit using descriptive statistics. The EQ-5D will be summarized by treatment and visit for each dimension. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary enpoints will be evaluated via periodic assessments over the entire course of the study. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 4 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Argentina |
| Brazil |
| Bulgaria |
| Canada |
| Colombia |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| South Africa |
| United States |
|
| 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
|
| The end of the study is defined as the date of the last protocol-specified visit/ assessment (including telephone contact) for the last subject in the study. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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