Asthma (Diagnosis), Moderate Asthma Exacerbation, Persistent Asthma
Conditions
Keywords
Asthma, Asthma Exacerbation, Anakinra, Kineret, Interleukin-1 Receptor Antagonist, IL-1 receptor blockade, Airway Inflammation, Persistent Asthma
Brief summary
In this single center, interventional pilot study, 40 participants at high risk for future exacerbation will be randomized to anakinra (v. placebo control) treatment for home administration as part of an asthma action plan (AAP) and monitored through their first moderate asthma exacerbation, triggering treatment dosing over a 26 week period. Key feasibility questions will be assessed in this pilot study to inform trial design and sample size selection for a future multi-site phase II clinical trial testing anakinra as a rescue treatment for moderate asthma exacerbations.
Detailed description
This pilot study will incorporate early intervention with the IL-1 receptor antagonist (IL-1RA), anakinra, as part of a home-based asthma action plan (AAP) at the start of a moderate exacerbation with the goal of preventing severe exacerbations requiring systemic steroids. The investigators will determine the feasibility of recruitment, enrollment, and retention for a trial that requires self administered injections; adherence to critical protocol operational tasks and rates of moderate exacerbations; and preliminary safety and efficacy of anakinra treatment during a moderate asthma exacerbation, with the goal of these findings supporting the development a hybrid decentralized phase II trial. 40 adults (≥18 years and \< 65 years) with persistent asthma that experienced an exacerbation within the prior 12 months requiring systemic steroid treatment will be enrolled, with the aim to randomize 20 women and 20 men. Up to 100 subjects will be screened to randomize 40 subjects. Patients are to receive anakinra or placebo during a moderate asthma exacerbation (defined by pre-specified criteria). Investigators will monitor symptom scores, lung function measurements, rescue medication use, systemic corticosteroid use, and healthcare utilization during exacerbations. Device training, blood collection, and nasal sample collection will also occur.
Interventions
DRUGAnakinra 100 Mg/0.67 Ml Inj Syringe
Active study treatment
DRUGSaline Placebo/0.67 Ml Inj Syringe
Placebo
Sponsors
University of North Carolina, Chapel Hill
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Subjects will be allocated to placebo or anakinra treatment using permuted block randomization with a block of size 4 (2 placebo, 2 anakinra)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of signed and dated informed consent form * Age ≥18 years * A history of physician-diagnosed persistent asthma or symptoms consistent with persistent asthma based on national or international guidelines for diagnosis and management of asthma. * Current use of controller therapy such as inhaled corticosteroid (ICS) or ICS in combination with long-acting beta agonist (LABA) * Asthma exacerbation requiring systemic corticosteroid therapy in the past 12 months * Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy or who have been amenorrheic for 12 months or more. * Asthma Impairment and Risk Questionnaire (AIRQ) Score \>2
Exclusion criteria
* Clinical contraindications: 1. Physician diagnosis of other chronic pulmonary disease including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema or congenital disorders of the lungs or airways. 2. History of undergoing bronchial thermoplasty. 3. Intubation for asthma in the last 12 months 4. History of malignancy except non-melanoma skin cancer within the last five years. 5. Any chronic medical condition considered by the PI as a contraindication to inclusion in the study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic or recurrent infections or immunodeficiency. 6. Mental illness or history of substance abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements. 7. History of smoking: i. Smoking \>1 time per week in the past year; ii. If ≥40 years old: Smoked ≥15 pack years; iii. If \<40 years old: Smoked ≥10 pack years; iv. Smoking equivalents of 1 pack cigarettes a day for 1 year: 1 cigar or pipe daily for 1 year; Hookah - 1 session per day for 1 year; E-cigarettes or vapes - 1 cartridge/tank/pod per day for 1 year; and active use of smoking/vaping marijuana, specified as once per week in the last year. 8. Allergy/sensitivity to study drugs or their formulations, including latex 9. Unwillingness to use reliable contraception if sexually active (IUD, birth control pills/patch, condoms). 10. Current participation in an interventional trial in which study administration was administered within the past 60 days or within 5 half-lives of the drug (whichever is greater) * Pregnancy, plans to get pregnant or nursing a baby. Female volunteers will be asked to use effective birth control (stable regimen of hormonal contraceptive use for at least 6 months, intrauterine device placement, or tubal ligation for at least 6 months through at least one week after study completion) and will provide a urine sample to test for pregnancy on study days. If the test is positive or the participant has reason to believe she may be pregnant, she will be dismissed from the study. Women who have been amenorrheic for 12 months may participate. Male volunteers will be asked to use condoms for the duration of the study through at least one week after study completion. * Usage of the following medications: 1. Use of daily systemic corticosteroid therapy for asthma control 2. Use of any immunomodulatory therapy within the preceding 12 months, including biologics that are approved for asthma. 3. Currently receiving allergen immunotherapy 4. Use of any immunosuppressant therapy within the preceding 12 months will be reviewed by the study physician. * Laboratory: Participants who meet the following criteria will be excluded from study: 1. Positive QuantiFERON-tuberculosis (TB) gold assay. Cases of indeterminate QuantiFERON-TB test results will require a second specimen to be drawn. 2. Baseline absolute neutrophil count (ANC) \<1.0 x 109/L for participants of African descent, \<1.5 x 109/L for other participants * Allergy/sensitivity to study drugs or their formulations, including latex. * History of anaphylaxis requiring epinephrine treatment * Inability or unwillingness of a participant to give written informed consent. * Inability or unwillingness to self-administer injectable medication (anakinra or placebo).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Anakinra on absolute change in morning PEF from baseline during moderate asthma exacerbation | Day 1 of treatment through day 10 after treatment | Area under the curve (AUC) of the absolute change from baseline, over the period of treatment day 1 through 10 days post-treatment day 1, calculated using the trapezoidal method, and comparing Anakinra to placebo treatment. |
| Study Design Feasibility - Percentage of participants who experience one moderate asthma exacerbation | The 6-month period from randomization to the end of study visit | Percent of randomized participants who experience one moderate asthma exacerbation (as defined by the participant's asthma action plan) during the 6-month study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Anakinra on Asthma Index during moderate asthma exacerbation | Day 1 of treatment to day 10 after treatment | Asthma Index is a continuous variable that reflects the magnitude and timing of changes in asthma control. Asthma scores are calculated using objective peak expiratory flow (PEF) and subjective symptom score elements over a 48-hour period. Asthma scores will be calculated over the period of treatment day 1 through 10 days post-treatment day 1 and subtracted from the mean Asthma score from a stable baseline 7-day period to obtain the Asthma Index. The area under the curve (AUC) of the Asthma Index will be calculated over the period of treatment day 1 through 10 days post-treatment day 1. Higher Asthma Index AUC values represent a greater cumulative burden of uncontrolled asthma relative to the individual's stable baseline (i.e., worse asthma control), while lower values represent better-maintained asthma control over the assessment period. |
| Intervention Feasibility - Mean number of participants enrolled per month | 18 months | Mean number of participants completing the screening visit and signing informed consent per month. |
| Intervention Feasibility - Mean number of participants randomized per month | 18 months | Mean number of participants completing the training and randomization visit per month. |
| Intervention Feasibility - Percentage of participants retained through completion of study | 24 months | Percentage of total randomized participants who complete visit 9 (end of study visit). |
| Study Design Feasibility - Percentage of participants completing daily PEF measurements | 24 months | Percentage of randomized participants who complete at least 75% of expected daily PEF measurements. |
| Fidelity to Study Intervention - Percentage of prescribed doses of study treatment that are self-administered by the participant | 24 months | Percentage of prescribed doses of study treatment that are completed through self-administration by the study participant during treatment visit 1 or treatment visit 2. |
| Percentage of participants requiring rescue systemic corticosteroid treatment | The 10 day period following the start of treatment for an exacerbation | Among participants who experience an exacerbation event, the percentage who require treatment with systemic corticosteroids for ongoing symptoms and/or PEF reduction. |
| Percentage of participants with rebound worsening of asthma exacerbation after study treatment | The 10 day period following the start of treatment for an exacerbation | Among participants who experience an exacerbation event, the percentage who experience rebound worsening of the asthma exacerbation will be reported. Rebound worsening of asthma exacerbation is defined as an initial improvement in symptoms, short acting beta-agonist (SABA) use and/or peak expiratory flow (PEF) after study treatment with subsequent deterioration shown by a decline in PEF, increased SABA use, or need for systemic corticosteroids during Visits T4-T7. |
| Percentage of participants experiencing an asthma exacerbation that requires emergency care | The 10 day period following the start of treatment for an exacerbation | Among participants who experience an exacerbation event, the percentage who require emergency care, defined as an unscheduled primary care visit, urgent care visit, or emergency department visit, will be reported. |
| Percentage of participants experiencing an asthma exacerbation that requires hospitalization. | The 10 day period following the start of treatment for an exacerbation | Among participants who experience an exacerbation event, the percentage who require hospitalization will be reported |
| Percentage of participants with post-treatment severe neutropenia. | 14 days following the start of treatment for an exacerbation | Among participants who inject study treatment for an exacerbation, the percentage with post-treatment severe neutropenia will be reported. A post treatment complete blood count (CBC) will be performed and severe neutropenia will be defined as an absolute neutrophil count (ANC) \< 500 cells/µL. |
| Percentage of participants experiencing serious infection | The 14 day period following the start of treatment for an exacerbation | Among participants who inject study treatment for an exacerbation, the percentage who experience a serious infection (including pneumonia, cellulitis, kidney or neurologic infections, and bacteria or sepsis) will be reported. |
| Percentage of participants experiencing an injection site reaction | The 14 day period following the start of treatment for an exacerbation | Among participants who inject study treatment for an exacerbation, the percentage who experience injection site reactions will be reported. |
| Percentage of accurately identified participants | Up to 24 months | Electronic medical record (EMR)-based data pulls will occur at intervals throughout the enrollment period to identify potentially eligible participants through a computable phenotype. The percentage of potentially eligible participants that were accurately identified through this computable phenotype will be reported. |
Countries
United States
Contacts
CONTACTChris Brooks
CONTACTCorinne Taylor
PRINCIPAL_INVESTIGATORMichelle Hernandez, MD
University of North Carolina, Chapel Hill
Outcome results
None listed