The primary objective of this study is to determine the ability of reslizumab (110 mg) administered subcutaneously (sc) once every 4 weeks to produce a corticosteroid-sparing effect (as demonstrated by percent reduction in daily OCS use) in patients…
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Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy variable and endpoint for this study is the categorized
percent reduction in the daily OCS dose during weeks 20 to 24 as compared with
the dose at the end of the optimization phase. Percent reduction will be
categorized as follows:
• 90% to 100%
• 75% to <90%
• 50% to <75%
• >0% to <50%
• No decrease in OCS, or loss of baseline asthma control during weeks 20
through 24, or discontinuation from study drug
Loss of baseline asthma control will be defined as FEV1 value of less than 80%
of baseline at the week 24 visit, or clinically significant worsening in ACQ-6
score (change in score of 0.5) at the week 24 visit compared with baseline,
and/or clinical asthma exacerbation during weeks 20 through 24.
Secondary outcome
The secondary efficacy variables and endpoints for this study are as follows:
• Proportion of patients achieving >=50% reduction in OCS dose at weeks 20 to 24
relative to the OCS dose at DoR/baseline, while maintaining asthma control
• Proportion of patients achieving dose reduction to <=5 mg daily dose at weeks
20 to 24, while maintaining asthma control
• Percent change from DoR/baseline in OCS dose at weeks 20 to 24
• Proportion of patients achieving less than 5 mg decrement in OCS dose (ie,
the minimal and non-responders) at weeks 20 to 24 compared with the OCS dose at
DoR/baseline, while maintaining asthma control
• Clinical asthma exacerbation related:
- Annualized rate of clinical asthma exacerbations requiring a burst of
systemic corticosteroid (injection, or if oral, at least a doubling from the
current OCS dose for at least 3 days); an asthma-specific hospital admission;
or an asthma-specific emergency department visit during the treatment period
(weeks 0 to 24)
• Proportion of patients discontinuing OCS at weeks 20 to 24, while maintaining
asthma control
Background summary
The study is for patients whose asthma is not adequately controlled on daily
ICS alone, the addition of long-acting beta- agonists (LABAs) or and/or other
controller therapies often provides additional control. There are currently
very few options for patients whose asthma is inadequately controlled on
ICS/LABA. The most severely affected patients with asthma may require daily
oral corticosteroid (OCS) doses to maintain asthma control (GINA 2014). Chronic
use of daily OCS is associated with the severe adverse effects of an iatrogenic
Cushing*s syndrome, including increased risk of infections, impaired growth in
children, hyperglycemia, low bone density, elevated blood pressure, cataracts,
and adrenal insufficiency. Risk can be decreased by maintaining patients on the
lowest possible dose of OCS and utilization of corticosteroid-sparing
strategies. For more information see background in protocol (section 1.1)
Study objective
The primary objective of this study is to determine the ability of reslizumab
(110 mg) administered subcutaneously (sc) once every 4 weeks to produce a
corticosteroid-sparing effect (as demonstrated by percent reduction in daily
OCS use) in patients with OCS-dependent asthma and elevated blood eosinophils,
without loss of asthma control.
The secondary objective
The secondary objective of this study is to evaluate the clinical benefits of
reslizumab in the context of OCS reduction.
Exploratory Objectives
The exploratory objectives for this study are:
• To evaluate the influence of the baseline level of the asthma biomarker
periostin in the blood on reslizumab efficacy
• To evaluate the relationship between biomarker and clinical efficacy
variables during reslizumab treatment
• To evaluate the relationship between drug concentration and measures of
safety and/or efficacy
• To evaluate the effect of cessation of reslizumab on asthma control
• To evaluate the effect of change in OCS dose on glycemic control and
metabolic factors in patients with OCS dependent asthma
• To evaluate the effect of OCS dose on Sinonasal Outcome Test (SNOT)-22 score
in patients with nasal polyps
Study design
This Double-Blind, Placebo-Controlled, Parallel-Group, is designed to evaluate
the Efficacy and Safety of Reslizumab Subcutaneous Dosing (110 mg Every 4
weeks) in Patients with Oral Corticosteroid Dependent Asthma and Elevated Blood
Eosinophils. Approximately 152 subjects will participate over approximately 62
weeks. The study consists of approximately 21 study visits, which include a
screening period of up to 2 weeks, an optimization period of up to 10 weeks
(during which your optimal dose of daily oral corticosteroids is determined), a
run-in period for at least 2 weeks, a treatment period of approximately 24
weeks and an 8-week follow-up visit. It is expected that the optimization
period will be shorter than 10 weeks for those patients who are at or near
their lowest effective dose of corticosteroid when entering the study. An
additional late follow up visit will be performed 28 weeks after your last dose
to collect extra blood samples.
The screening period (up to 2 weeks) for eligibility determination may begin
after the subject signs the informed consent form. Subjects will undergo safety
and other assessments to confirm OCS dependent asthma.
Optimization period (up to 10 weeks) will determine the patient*s minimal
effective OCS requirement. The patient*s previous OCS will be standardized to
an equivalent dose and regimen of prednisone to facilitate optimization. It is
expected that the optimization period will be shorter than 10 weeks for those
patients who are at or near their optimal corticosteroid dose at enrollment.
The Run-in period (for at least 2 weeks). Patients whose minimal effective OCS
dose remains between >=5 mg and <= 40 mg at the end of optimization may advance
to run-in (for at least 2 weeks). During run-in, patients will continue to keep
their daily asthma control diary and a PEF meter to perform daily
self-monitoring of asthma symptoms while maintaining their minimally effective
OCS dose and previous background asthma medications unchanged.
The Treatment Period (approximately 24 weeks) consist of the following:
• Induction: The minimally effective dose of OCS will be maintained, unchanged,
during the first 4 weeks of the treatment period.
• OCS reduction: The minimally effective OCS dose will be reduced per protocol
at scheduled clinic visits from the beginning of week 5 (ie, end of the
induction period) through week 20, as long as all criteria in are met. The last
possible dose reduction can occur at week 20.
If the OCS dose could not be decreased, it should be held constant, or may be
increased to a previous level, at the investigator*s discretion, until dose
reduction criteria are met.
• Maintenance: OCS will be held stable from week 20 through EOT week 24.
Follow up Period for immunogenicity testing will be performed 28 weeks after
the last dose of study drug.
Intervention
Reslizumab will be administered as a fixed dose of 110 mg, as a sc injection in
the upper arm(s) once every 4 weeks.
Study burden and risks
8x Pregnancy test
20x Blood samples
1x Urine sample
19x Physical Examination
19x Vital signs
3x Height and weight
2x ECG
10x Lung function tests
9x PK samples (3 mL or 1 teaspoon blood will be taken)
1x allergy test
8x Questionnaires
6x Study medication administration
Electronic asthma control diary
In general, reslizumab was well tolerated over the range of doses evaluated
(i.e., from 0.03 through 3.0 mg/kg). In completed clinical studies, the
majority of adverse events (symptoms) were mild to moderate in severity, and
most adverse events were considered unrelated to study drug, as determined by
the investigator. Overall, the nature and occurrence of the reported
treatment-related adverse events did not raise any specific safety concerns.
Side effects can vary from person to person. In general, many side effects go
away after a drug is stopped but in some cases the side effects may be severe
and/or may never go away. Side effects might also go away without stopping a
drug.
Uncommon side effects (affect 1 to 10 users in 1,000)
• Anaphylaxis reactions (severe systemic allergic reaction that can include
itching, trouble breathing, wheezing, fever, shivering, blood pressure changes,
dizziness, headache, nausea, vomiting, abdominal discomfort, skin rash,
redness, or swelling)
• Myalgia (muscle aches). Muscle aches occurred slightly more frequently in
patients treated with reslizumab, but there was no evidence of muscle injury.
Additional safety information:
In addition to side effects that have been identified with reslizumab, the
following are potential concerns that may be related to the use of a biologic,
anti-IL5 monoclonal antibody product (like reslizumab). These have not been
identified as risks related to reslizumab in clinical trials:
• Parasitic worm (helminthic) infections: Eosinophils, a type of white blood
cell that is reduced by anti-IL5 treatment, may be involved in the response of
the immune system to parasitic worm infections. Therefore, the ability to fight
infections related to worms may be reduced by a drug that lowers eosinophil
levels.
In the reslizumab clinical trials, which included patients from geographical
regions where parasitic worm infections are common, no parasitic worm
infections were reported.
• Increased potential for cancer: The role of eosinophils and IL-5 in
protection against cancer is unknown. Use of any drug that impacts the immune
system may raise a concern about cancer. However, in clinical trials, there was
no evidence of an increased risk of cancer in patients who were treated by
reslizumab.
• Anti-drug antibodies (ADA) are antibodies that are made by the immune system
against certain drugs, and are not unexpected with biologics. The concern is
that these antibodies would stop the drug from working properly or lead to
certain hypersensitivity (allergic) reactions. Antibodies to reslizumab have
been detected infrequently in reslizumab-treated patients, and did not have
observed impact on treatment effectiveness or safety.
There is a risk that your asthma will not get better and that your symptoms or
condition may worsen or not improve. However, your study doctor will follow
you carefully and observe any unwanted effects or problems. You will continue
your current asthma medications during the study.
Moores Road 41
Frazer, Pennsylvania 19355
US
Moores Road 41
Frazer, Pennsylvania 19355
US
Listed location countries
Age
Inclusion criteria
a. The patient is male or female, 12 through 75 years of age, with a previous diagnosis of asthma. Patients 12 to <18 years of age are excluded from participating in South Korea, The Netherlands and Argentina, and patients 66 years of age and older are excluded from participating in South Korea.
b. Written informed consent is obtained. A patient 12 through <18 years of age must provide assent and his/her parent(s) or legal guardian(s) must provide consent.
c. The patient continues to require an average daily maintenance dose of OCS or equivalent for asthma of between 5 and 40 mg during the 3 months prior to screening. Patients on an OCS dose of >40 mg at screening who the investigator believes may be able to decrease OCS dose to <=40 mg during the optimization period may also be enrolled. Note: every-other-day dosing that is within this daily average (ie, 10 to 80 mg) is allowed.
d. The patient has a documented blood eosinophil level of at least 300/*L during the previous 12 months while on at least medium dose inhaled corticosteroid (ICS) (eg, >=440 µg/day of fluticasone propionate or equivalent daily), or >=300/*L at screening while on chronic OCS or that becomes manifest during the OCS optimization period or at the week -2 visit (end of optimization period/beginning of run-in period).
e. The patient has required at least 880 µg of inhaled fluticasone propionate or equivalent daily PLUS another controller(s) (eg, long-acting beta-adrenergic agonist [LABA], long-acting anti-muscarinic antagonist [LAMA], leukotriene inhibitor, or theophylline), or documented intolerance to another controller, for at least 6 months prior to the screening visit. For a fixed-dose ICS/LABA preparation, the highest labeled dose in that region will satisfy this criterion. For patients 12 through <18years of age, the ICS dose must be >=440 µg/day of fluticasone propionate or equivalent daily. Note: the dose and regimen of asthma controllers and any allergen immunotherapy should have been stable during the 30 days prior to signing the Informed Assent Form/Informed Consent Form (ICF).
f. The patient has FEV1 reversibility of at least 12% and an absolute change of at least 200 mL after administration of inhaled SABA according to the standard American Thoracic Society (ATS) or European Respiratory Society (ERS) protocol. Given the refractory nature of the disease in this population and the influence of high background controller medications on reversibility testing, documented FEV1 reversibility of 12% or a provocation concentration producing a 20% fall in FEV1 for methacholine of <=8 mg/mL within 24 months of the screening visit, and performed according to the standard ATS/ERS procedures, would fulfill this criterion.
g. A woman/girl of childbearing potential (not surgically sterile or 2 years postmenopausal) must have exclusively same-sex partners or use medically acceptable methods of birth control and must agree to continue use of this method for the duration of the study and for 5 months after the last study drug dose. Acceptable methods of birth control include intrauterine device, systemic hormonal contraceptive (oral, implanted, transdermal, or injected), barrier method with spermicide, abstinence, and partner vasectomy.
h. The patient must be willing and able to comply with study restrictions, willing and able to perform requisite procedures and to remain at the clinic for the required duration during the study period, and willing to return to the clinic for the follow up evaluation as specified in this protocol.
i. Except for the OCS, which will be adjusted per protocol, the patient must maintain his/her usual asthma controller regimen without change throughout the screening, optimization, run-in, and treatment periods.
Exclusion criteria
a. The patient has any clinically significant, uncontrolled medical condition (treated or untreated) that would interfere with the study schedule or procedures and interpretation of efficacy results or would compromise the patient*s safety.
b. The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, interstitial lung disease, bronchiectasis eosinophilic granulomatosis with polyangiitis [also known as Churg-Strauss syndrome], or allergic bronchopulmonary aspergillosis).
c. The patient has a known hypereosinophilic syndrome.
d. The patient has a history of any malignancy within 5 years of the screening visit, except for treated and cured non-melanoma skin cancers.
e. The patient is pregnant or intends to become pregnant during the study or is a lactating woman. Any woman becoming pregnant will be withdrawn from the study.
f. The patient required treatment for an asthma exacerbation within 4 weeks of screening.
g. The patient is a current smoker (ie, has smoked within the last 6 months prior to screening) or has a smoking history >=10 pack-years.
h. The patient is currently using any systemic immunosuppressive or immunomodulatory biologic (eg, anti immunoglobulin E monoclonal antibody [mAb] or other mAb [eg, mepolizumab] or soluble receptor) or non-biologic (eg, methotrexate, cyclosporine), except maintenance OCS for the treatment of asthma. Previous use of such agents that occurred >5 half-lives from the screening visit may be allowed, if approved by the medical monitor.
i. The patient participated in a clinical study within 30 days or 5 half-lives of the investigational drug before screening, whichever is longer.
j. The patient was previously exposed to benralizumab within 12 months of screening.
k. The patient was previously exposed to reslizumab
l. The patient has a history of immunodeficiency disorder including human immunodeficiency virus.
m. The patient has current suspected drug and/or alcohol abuse.
n. The patient has had an active helminthic parasitic infection or was treated for one within 6 months of screening.
o. The patient has a history of allergic reactions or hypersensitivity to any component of the study drug.
p. The patient has a history of latex allergy. (The current prefilled syringe device has a natural rubber component to the needle shield.)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-001580-39-NL |
| CCMO | NL54883.075.15 |