PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study

Overview

About this study

The purpose 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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. 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 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 PC20 ≤16 mg/ml, or 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 THC
(tetrahydrocannabinol) 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 Exclusion Criteria:

Participants who meet the following criteria will be excluded from the study:

1. Hemoglobin <10 g/dL

2. Absolute Neutrophil Count (ANC) <1000/µl for black participants, <1500/µl for other
participants

3. Lymphocytes <500/µl

4. Platelet count <100,000/µl

5. Alanine Transaminase (ALT)/Aspartate Aminotransferase (AST) >2x upper limits of normal
(ULN)

6. Bilirubin ≥2x ULN

7. Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 sq m

8. Positive Human Immunodeficiency Virus, Types 1 & 2 (HIV 1&2) Ab/Ag immunoassay
followed by a confirmatory positive test (Geenius? HIV-1/HIV-2 antibody
differentiation immunoassay)

9. Positive Hepatitis B surface Ag (active infection) or Hepatitis B core total antibody
(marker of past infection that could reactivate)

10. Positive Hepatitis C RNA test following positive Hepatitis C Antibody

11. EKG with significant clinical findings

A positive QuantiFERON-TB (tuberculosis) Gold test requires further screening. A
participant may be included in PrecISE if at least one of the following criteria are met:

1. A chest radiograph (CXR) done within the last six months of the test that shows no
evidence of active TB

2. A chest CT scan done within the last six months of the test that shows no evidence of
active TB

3. Documentation of adequate treatment for latent TB In cases of an indeterminate
QuantiFERON-TB test result, a second blood specimen must be drawn. A chest x-ray is
not required if the participant has a negative QuantiFERON-TB Gold test.

Comorbid Conditions:

Comorbidities are commonly present in severe asthma. Specific questionnaires will be used
to identify common comorbidities as follows:

1. Sleep apnea: STOP-BANG

2. GERD (GERD- Questionnaire)

3. VCD (Pittsburgh vocal cord dysfunction index)

4. Chronic Rhinitis Sinusitis (Sinonasal questionnaire-SNQ5)

5. Depression-Anxiety (Hospital anxiety and depression Scale: HADS) These questionnaires
are best used as screening tools. As such they typically have high sensitivity but
relatively low specificity. Many of their symptoms overlap with the symptoms reported
by participants with asthma who do not suffer from these conditions. Therefore,
participants who meet the established cut offs for these questionnaires will need to
be evaluated by the investigator to consider the clinical significance of the positive
questionnaire based on history and physical and available testing. The investigator
will need to judge the presence, severity and control of a specific condition and
determine if it is sufficiently controlled to keep the participant in the PrecISE
protocol. If the comorbid condition(s) is/are not adequately controlled, the
investigator may refer the participant for further evaluation/treatment, prior to
enrollment in PrecISE. Rescreening is permitted (after at least four weeks) to
determine if the participant is able to move forward in PrecISE once the comorbid
condition(s) is/are under adequate control. It is expected that some of the
participants may also have other conditions such as cardiovascular disease, diabetes
and obesity. These should be evaluated clinically as part of the complete history and
physical done at initial evaluation. Their inclusions should be based on the
investigator clinical judgement in line with good clinical practice principles.

Eligibility last updated 6/28/22. Questions regarding updates should be directed to the study team contact.

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Matthew Rank, M.D.

Open for enrollment

Contact information:

Temeka Simmons

(480) 301-9224

Simmons.Temeka@mayo.edu

More information

Publications

  • Tools for quantification of asthma severity are limited. Read More on PubMed
  •  To determine the frequency of prescriptions for short term use of oral corticosteroids, and adverse events (sepsis, venous thromboembolism, fractures) associated with their use. Retrospective cohort study and self controlled case series. Nationwide dataset of private insurance claims. Adults aged 18 to 64 years who were continuously enrolled from 2012 to 2014. Rates of short term use of oral corticosteroids defined as less than 30 days duration. Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation. Of 1 548 945 adults, 327 452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P<0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001). One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events. Read More on PubMed
  • Phenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids. Read More on PubMed
  • Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. Read More on PubMed
  • The size of the placebo response in type 2 diabetes (T2DM) treatment and its relation to the route of drug administration have not been systematically reviewed. We aimed to determine weight loss, change in HbA1c and incidence of adverse events after treatment with injectable placebo GLP-1 receptor agonist (GLP-1ra), compared with oral placebo DPP-4 inhibitor (DPP-4i) and placebo SGLT-2 inhibitor (SGLT-2i). Read More on PubMed
  • The placebo effect is a complex phenomenon occurring across a variety of clinical conditions. While much placebo research has been conducted in diseases defined by self-report such as depression, chronic pain, and irritable bowel syndrome (IBS), asthma has been proposed as a useful model because of its easily measured objective outcomes. Studies examining the placebo response in asthma have not only contributed to an understanding of the mechanisms behind the placebo response but also shed an interesting light on the current treatment and diagnosis of asthma. This paper will review current literature on placebos in general and specifically on the placebo response in asthma. It focuses on what we know about the mechanisms behind the placebo effect, whether there is a specific portion of the population who responds to placebos, which patient outcomes are influenced by the placebo effect, and whether the effect can be augmented. Read More on PubMed
  • There is increasing interest in discovering individualized treatment rules for patients who have heterogeneous responses to treatment. In particular, one aims to find an optimal individualized treatment rule which is a deterministic function of patient specific characteristics maximizing expected clinical outcome. In this paper, we first show that estimating such an optimal treatment rule is equivalent to a classification problem where each subject is weighted proportional to his or her clinical outcome. We then propose an outcome weighted learning approach based on the support vector machine framework. We show that the resulting estimator of the treatment rule is consistent. We further obtain a finite sample bound for the difference between the expected outcome using the estimated individualized treatment rule and that of the optimal treatment rule. The performance of the proposed approach is demonstrated via simulation studies and an analysis of chronic depression data. Read More on PubMed
  • Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. Read More on PubMed
  • For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking. Read More on PubMed
  • The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma. Read More on PubMed
  • Information that enhances expectations about drug effectiveness improves the response to placebos for pain. Although asthma symptoms often improve with placebo, it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit. Read More on PubMed
  • More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children. Read More on PubMed
  • In adaptive treatment strategies, the treatment level and type is repeatedly adjusted according to ongoing individual response. Since past treatment may have delayed effects, the development of these treatment strategies is challenging. This paper advocates the use of sequential multiple assignment randomized trials in the development of adaptive treatment strategies. Both a simple ad hoc method for ascertaining sample sizes and simple analysis methods are provided. Read More on PubMed
  • The construct validity of a quantitative work productivity and activity impairment (WPAI) measure of health outcomes was tested for use in clinical trials, along with its reproducibility when administered by 2 different methods. 106 employed individuals affected by a health problem were randomised to receive either 2 self-administered questionnaires (self administration) or one self-administered questionnaire followed by a telephone interview (interviewer administration). Construct validity of the WPAI measures of time missed from work, impairment of work and regular activities due to overall health and symptoms, were assessed relative to measures of general health perceptions, role (physical), role (emotional), pain, symptom severity and global measures of work and interference with regular activity. Multivariate linear regression models were used to explain the variance in work productivity and regular activity by validation measures. Data generated by interviewer-administration of the WPAI had higher construct validity and fewer omissions than that obtained by self-administration of the instrument. All measures of work productivity and activity impairment were positively correlated with measures which had proven construct validity. These validation measures explained 54 to 64% of variance (p less than 0.0001) in productivity and activity impairment variables of the WPAI. Overall work productivity (health and symptom) was significantly related to general health perceptions and the global measures of interference with regular activity. The self-administered questionnaire had adequate reproducibility but less construct validity than interviewer administration. Both administration methods of the WPAI warrant further evaluation as a measure of morbidity. Read More on PubMed
  • In this paper, we introduce a new type of tree-based method, reinforcement learning trees (RLT), which exhibits significantly improved performance over traditional methods such as random forests (Breiman, 2001) under high-dimensional settings. The innovations are three-fold. First, the new method implements reinforcement learning at each selection of a splitting variable during the tree construction processes. By splitting on the variable that brings the greatest future improvement in later splits, rather than choosing the one with largest marginal effect from the immediate split, the constructed tree utilizes the available samples in a more efficient way. Moreover, such an approach enables linear combination cuts at little extra computational cost. Second, we propose a variable muting procedure that progressively eliminates noise variables during the construction of each individual tree. The muting procedure also takes advantage of reinforcement learning and prevents noise variables from being considered in the search for splitting rules, so that towards terminal nodes, where the sample size is small, the splitting rules are still constructed from only strong variables. Last, we investigate asymptotic properties of the proposed method under basic assumptions and discuss rationale in general settings. Read More on PubMed
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CLS-20490396

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