Asthma
Conditions
Brief summary
The primary objective of this study is to evaluate several interventions given to participants with severe asthma. Interventions are administered in a crossover manner with 16-week treatment periods followed by 8 to 16 week washout.
Detailed description
PrecISE is a clinical study sponsored by the U.S. National Heart, Lung, and Blood Institute (NHLBI) to investigate several treatments for severe asthma. PrecISE will enroll 600 adults and teenagers (ages 12 years and older) with severe asthma who have symptoms that are not well-controlled on high dose of inhaled corticosteroids including those who have frequent asthma attacks. Each person who agrees to enroll in the PrecISE study will receive several treatments for research purposes based on their type of severe asthma. The goal of PrecISE is to understand how to treat different types of severe asthma, by using precision medicine. Precision medicine is an approach that targets treatments to defined subgroups of patients who share similar characteristics, for example, patients with a certain genetic variation or patients with high number of blood eosinophils. Researchers from over 30 locations across the US are involved in PrecISE.
Interventions
DRUGMCT
Mix 2-5 packets daily into liquid or food for 16 weeks.
DRUGClazakizumab
12.5 mg subcutaneous injection given once every 4 weeks for 16 weeks. Lab driven dose reductions will be made based on safety lab data. If criteria are met for dose reduction, the participant will be reduced to a 6.25 mg dose.
DRUGBroncho-Vaxom
7 mg taken orally once a day, on an empty stomach, for 16 weeks
DRUGImatinib Mesylate
Two 100 mg tablets orally once a day with a meal and an 8 oz glass of water for 2 weeks. If the drug is well tolerated, participants will titrate up to four 100 mg tablets once a day with a meal and an 8 oz glass of water for 14 weeks. Safety labs will be collected at each study visit to monitor the tolerability of each participant.
DRUGCavosonstat
50 mg capsule orally twice a day for 16 weeks.
OTHERPlacebo
MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets daily into liquid or food for 16 weeks. Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks for 16 weeks. Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: Two 100 mg placebo tablets orally once a day with a meal and an 8 oz glass of water for 2 weeks. Then four 100 mg placebo tablets once a day with a meal and an 8 oz glass of water for 14 weeks. Cavosonstat Matching Placebo: 50 mg matching placebo capsule orally twice a day for 16 weeks.
Sponsors
University of North Carolina, Chapel Hill
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Treatment sequence will be randomly assigned as either test treatment followed by matching placebo or vice-versa.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form 2. Started willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, age ≥ 12 years 4. No change in asthma medications for the past 2 months and use of medium or high dose inhaled corticosteroids (ICS) (defined by Table 1A) + an additional asthma controller/biologic (defined in Tables 1B and 1C). Participants entered into the run-in on medium dose ICS will be switched to high dose ICS. They must meet all entry criteria at the time of randomization including the criteria for uncontrolled asthma as assessed by symptoms during the two weeks prior to the randomization. 5. Baseline poor or uncontrolled asthma, defined as meeting at least one of the following: 1. Forced Expiratory Volume in one second (FEV1) \<80% predicted (for adults ≥18) or FEV1\<90% (pediatric participants \<18) AND with 12% bronchodilator reversibility 2. Poor symptom control - Asthma Control Questionnaire (ACQ-6) Score ≥1.5 3. ≥1 exacerbation defined as a documented burst of systemic corticosteroids (\>3 days for adults and adolescents or \>1 day for adolescents treated with dexamethasone) in prior year for those not receiving chronic oral corticosteriod (OCS) or an increase in \>50% of baseline corticosteroid dose for ≥3 days in those receiving chronic OCS. * For patients on a biologic agent, at least one asthma exacerbation must have occurred at least 2 months after the initiation of the biologic agent. The definition of acceptable documentation for asthma exacerbations can be found in Section 6.5.3. 6. Evidence of asthma demonstrated by either bronchodilator reversibility or methacholine responsiveness either during the run-in or by historical evidence of either criterion if testing was performed under the same standards of the PrecISE Network at a PrecISE recruitment center. These criteria are defined as: 1. An increase in FEV1 ≥12% (and 200 ml) after up to 8 puffs of albuterol OR 2. Positive methacholine defined as provocative concentration causing a 20% decrease in FEV1 (PC20) ≤16 mg/ml, or provocative dose causing a 20% decline in FEV1 (PD20) ≤400 mcg/ml 7. Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout study duration 8. Owns a device compatible with the eDiary system used for CompEx, that is, an iOS 11+ device such as iPhone, iPad or iPod, or a smartphone or tablet running on Android 5.0+
Exclusion criteria
1. Current participation in an interventional trial (e.g. drugs, diets, etc.) 2. Enrollment in a clinical trial where the study medication was administered within the past 60 days or within 5 half-lives (whichever is greater) 3. Physician diagnosis of other chronic pulmonary disorders associated with asthma-like symptoms, including, but not limited to, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways 4. Receiving one or more immune-modulating therapies for diseases other than asthma 5. Receiving methotrexate, mycophenolate (CellCept®), or azathioprine (Imuran®) 6. Receiving aero allergen immunotherapy and not on at least 3 months of maintenance allergen immunotherapy 7. Underwent a bronchial thermoplasty within the last two years 8. Born before 35 weeks of gestation 9. Uncontrolled hypertension, defined as systolic blood pressure \>160 mm/Hg, or diastolic blood pressure \>100 mm/Hg 10. History of malignancy except non-melanoma skin cancer within the last five years 11. History of smoking 1. If \<30 years old: Smoked for ≥5 pack-years\* * Can still be enrolled if \<30, smoked \<5 5 pack years and none in past year, and normal (negative) urine cotinine 2. If 30-39 years old: Smoked for ≥10 pack years * Can still be enrolled if ≥30, smoked \<10 pack years and none in past year, provided participant demonstrates a normal (negative) urine cotinine 3. If ≥40 years old: Smoked ≥15 pack years * Can still be enrolled if ≥40 years old, smoked \<15 pack years and none in the last year, provided participant demonstrates normal (negative) urine cotinine. Patients with a smoking history of ≥10 to \<15 pack years will also need to demonstrate a normal Diffusing Capacity for Carbon Monoxide (DLCO) (\>70% predicted) \* Smoking equivalent pack years. One pack of cigarettes a day for 1 year is equivalent to: <!-- --> 1. 1 cigar or pipe per day for 1 year 2. Smoked hookah or shisha =1 session per day for 1 year 3. Vaped e-cigarettes =0.5 mLs e-liquid per day for 1 year, or =1 cartridge/tank/pod per day for 1 year 4. 1 use of marijuana per day for 1 year 12. Active use of any inhalant \>1 time per month in the past year 1. Active smoking of conventional tobacco, inhaling of marijuana or other drugs, or vaping of e-cigarettes or vape pods \>1 time per month in the past year 2. Any form of tobacco qualifies, such as: 1 cigarette, 1 hookah or shisha sessions, 1 cigar, 1 pipe, etc. 3. Any electronic (e)-device included: e-cigarette e-cig, mod, vape pen, JUUL vaping device, e-cigar, e-hookah, e-pipe, vape pods, etc. 4. Any form of inhaled marijuana, including smoking marijuana leaves or inhaling tetrahydrocannabinol (THC) via e-cigarette or device 13. Substance abuse within the last year 14. Unwillingness to practice medically acceptable birth control or complete abstinence during the study, current pregnancy, or lactation. Medically acceptable birth control/abstinence is defined as: 1. Career, lifestyle, or sexual orientation precludes intercourse with a male partner 2. For those in a monogamous relationship that precludes sexual activity with other partners, one of the sexual partners has been sterilized by vasectomy (in males) or hysterectomy and/or bilateral salpingo-oophorectomy (in females) 3. Use of highly effective methods of birth control defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Contraception should be used for at least 1 month prior to screening, throughout study participation and for an additional 16 weeks after the end of the final test treatment. * Pregnancy tests will be given to each female participant prior to study enrollment and at each clinic visit * Each male participant will agree to inform his sexual partner(s) of the potential for harm to an unborn child. If a sexual partner becomes pregnant while he is participating in the study, he will notify study staff within 24 hours of receiving medical confirmation. His partner will be advised to promptly notify her doctor * Any pregnancy (of a participant or a partner) will be monitored for adverse events with respect to pregnancy outcome until one month after birth. 15. Requirement for daily systemic corticosteroids above 10 mg of prednisone (or equivalent) per day for the past 2 months 16. Respiratory infection within 1 month of screening 17. Intubation for asthma in the last 12 months 18. Use of warfarin, current or last 30 days 19. Any clinically significant abnormal findings in the history, physical examination, vital signs, electrocardiogram, hematology or clinical chemistry during run-in period, which in the opinion of the site investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study 20. Additional exclusions for specific interventions (and not for others) are listed in the Appendices I-VI, Section 5.2 Safety
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in One Second (FEV1) Percent Predicted | Measured at 16 weeks after the start of treatment. | Assessed prior to bronchodilator administration. Efficacy analyses will compare the end-of-period outcome values between test treatment and placebo. |
| The Juniper Asthma Control Questionnaire (ACQ-6) | Measured at 16 weeks after the start of treatment. | Asthma symptom control is assessed via ACQ-6, the average score of these six items (range 0-6). The seven-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled'. Negative change from baseline values indicate improved asthma control. Efficacy analyses will compare the end-of-period outcome values between test treatment and placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CompEx Events Per Year | Assessed over 16 weeks of treatment | Composite outcome with exacerbations (CompEx) is an outcome specific to asthma and chronic obstructive pulmonary disease (COPD) that combines clinically-relevant deteriorations with exacerbations. Deterioration events defined based on daily recordings of peak expiratory flow (PEF) morning/evening (L/min), reliever use morning/evening (doses), symptoms morning/evening (score 0-3) from twice-daily recordings. Participants are asked to describe their morning and evening symptoms using the following scale: 0-No symptoms to report, 3-I could not sleep because of my asthma/I could not perform my normal activities because of my asthma. |
| Forced Vital Capacity (FVC) Pre-bronchodilation | Measured at 16 weeks after the start of treatment. | Assessed prior to bronchodilator administration |
| FEV1 % Predicted Post-bronchodilation | Measured at 16 weeks after the start of treatment. | Assessed after 4 puffs of bronchodilator administration |
| Exacerbations | Assessed over 16 weeks of treatment | Annualized rate of severe exacerbations during the 16-week treatment periods, modified intent-to-treat (mITT) population. An asthma exacerbation in PrecISE is defined as a worsening of asthma requiring the use of a systemic corticosteroid (at least 3 days of treatment) to prevent a serious outcome. |
| Number of Participants With At Least One Asthma-Free Day | Assessed over 16 weeks of treatment | An asthma free day is a day where 1) there is no use of albuterol rescue (excluding the use of albuterol as pre-exercise treatment), 2) no daytime or nighttime asthma symptoms, 3) no peak expiratory flow of less than 80% of the predetermined reference value. |
| Number of Participants With At Least One Symptom-free Day | Assessed over 16 weeks of treatment | A symptom free day is a day with no asthma symptoms (symptom score = 0) for both morning and evening daily diary entries. |
| Healthcare Utilization | Assessed over 16 weeks of treatment | The combined total number of: asthma-specific Emergency Department visits, asthma-specific hospital admissions, and asthma-specific ICU admissions. The investigators report the number of participants with at least one asthma-specific Emergency Department visit, asthma-specific hospital admission, or asthma-specific ICU admission |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAnastasia Ivanova, PhD
University of North Carolina, Chapel Hill
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 16 |
| Race (NIH/OMB) American Indian or Alaska Native | 15 Participants |
| Race (NIH/OMB) Asian | 18 Participants |
| Race (NIH/OMB) Black or African American | 83 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 237 Participants |
| Region of Enrollment United States | 358 Participants |
| Sex: Female, Male Female | 232 Participants |
| Sex: Female, Male Male | 126 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 950 | 2 / 99 | 0 / 57 | 0 / 126 | 0 / 66 | 0 / 133 | 0 / 92 | 0 / 120 | 0 / 76 | 0 / 118 | 0 / 77 |
| other Total, other adverse events | 74 / 950 | 65 / 99 | 40 / 57 | 82 / 126 | 40 / 66 | 105 / 133 | 65 / 92 | 80 / 120 | 49 / 76 | 92 / 118 | 52 / 77 |
| serious Total, serious adverse events | 19 / 950 | 10 / 99 | 4 / 57 | 4 / 126 | 4 / 66 | 12 / 133 | 9 / 92 | 3 / 120 | 5 / 76 | 9 / 118 | 6 / 77 |
Outcome results
None listed