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

Sponsor
University of North Carolina, Chapel Hill (Other)
Overall Status
Recruiting
CT.gov ID
NCT04129931
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
600
Enrollment
29
Locations
5
Arms
41.4
Anticipated Duration (Months)
20.7
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
600 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
Treatment sequence will be randomly assigned as either test treatment followed by matching placebo or vice-versa.Treatment sequence will be randomly assigned as either test treatment followed by matching placebo or vice-versa.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study
Actual Study Start Date :
Dec 19, 2019
Anticipated Primary Completion Date :
Jun 1, 2023
Anticipated Study Completion Date :
Jun 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Medium Chain Triglycerides (MCT)

Participants in this arm will receive Medium Chain Triglycerides (MCT) powder packets (10 g each) at each treatment visit at any point in the study. Participants will mix 1-2 packets of MCT supplement powder into liquids or semi-solid food and ingest 3 times a day during the 16-week treatment period. Participants will be randomized to the treatment sequence and will receive either the active MCT or the matching placebo first or vice versa.

Drug: MCT
Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily
Other Names:
  • Breathe Better Diet (BBD)

    • Other: Placebo
    MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily 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.
    Experimental: Clazakizumab

    Participants randomized to this arm will receive a 12.5 mg dose of Clazakizumab via a subcutaneous injection at every study visit, every 4 weeks, during the 16-week treatment period at any point in the study. Participants will be randomized to the treatment sequence and will receive either the active Clazakizumab or the matching placebo first or vice versa.

    Drug: Clazakizumab
    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.
    Other Names:
  • Anti-interleukin 6 monoclonal antibody
  • Anti-IL-6 mAb
  • BMS-945429
  • ALD518

    • Other: Placebo
    MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily 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.
    Experimental: Broncho-Vaxom

    Participants randomized to this arm will receive 7 mg of Broncho-Vaxom once a day on an empty stomach for the 16-week treatment period duration at any point in the study. Participants will be randomized to the treatment sequence and will receive either the active Broncho-Vaxom or the matching placebo first or vice versa.

    Drug: Broncho-Vaxom
    7 mg taken orally once a day, on an empty stomach, for 16 weeks
    Other Names:
  • OM-85 BV VEGETAL

    • Other: Placebo
    MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily 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.
    Experimental: Imatinib

    At any point in the study, participants randomized to this arm will take two 100 mg Imatinib tablets orally once a day with a meal and an 8 oz glass of water for 2 weeks. Participants will then take four 100 mg tablets once a day with a meal and an 8 oz glass of water for 14 weeks. Participants will be randomized to the treatment sequence and will receive either the active Imatinib or the matching placebo first or vice versa.

    Drug: Imatinib 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.
    Other Names:
  • Gleevec
  • Zoleta
  • Glivec
  • Ziatir

    • Other: Placebo
    MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily 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.
    Experimental: Cavosonstat

    Participants randomized to this arm will take one 50 mg Cavosonstat capsule orally twice a day for the 16-week treatment period duration at any point in the study. Participants will be randomized to the treatment sequence and will receive either the active Cavosonstat or the matching placebo first or vice versa.

    Drug: Cavosonstat
    50 mg capsule orally twice a day for 16 weeks.
    Other Names:
  • N91115

    • Other: Placebo
    MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily 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.

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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.

    3. CompEx events [Assessed over 16 weeks of treatment]

      CompEx is a composite outcome specific to asthma that combines clinically-relevant deteriorations captured by diary events with exacerbations. CompEx events include exacerbations and 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 will be asked to describe their morning and 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.

    Secondary Outcome Measures

    1. Forced Vital Capacity (FVC) pre-bronchodilation [Measured at 16 weeks after the start of treatment.]

      Assessed prior to bronchodilator administration

    2. FEV1 post-bronchodilation [Measured at 16 weeks after the start of treatment.]

      Assessed after bronchodilator administration.

    3. Time to first exacerbation [Assessed over 16 weeks of treatment]

    4. Symptom free days [Assessed over 16 weeks of treatment]

    5. Asthma free days [Assessed over 16 weeks of treatment]

    6. Healthcare utilization [Assessed over 16 weeks of treatment]

      Asthma-specific Emergency Department visits, asthma-specific hospital admissions, and asthma-specific ICU admissions.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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:

    6. FEV1 <80% predicted (for adults ≥18) or FEV1<90% (pediatric participants <18) AND with 12% bronchodilator reversibility

    7. Poor symptom control - Asthma Control Questionnaire ( ACQ-6) Score ≥1.5

    8. ≥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.

    1. 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:

    2. An increase in FEV1 ≥12% (and 200 ml) after up to 8 puffs of albuterol OR

    3. Positive methacholine defined as PC20 ≤16 mg/ml, or PD20 ≤400 mcg/ml

    4. Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout study duration

    5. 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

    12. 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
    1. 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
    1. 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

    5. Active use of any inhalant >1 time per month in the past year

    6. 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

    7. Any form of tobacco qualifies, such as: 1 cigarette, 1 hookah or shisha sessions, 1 cigar, 1 pipe, etc.

    8. Any electronic (e)-device included: e-cigarette e-cig, mod, vape pen, JUUL vaping device, e-cigar, e-hookah, e-pipe, vape pods, etc.

    9. Any form of inhaled marijuana, including smoking marijuana leaves or inhaling THC (tetrahydrocannabinol) via e-cigarette or device

    10. Substance abuse within the last year

    11. 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:

    12. Career, lifestyle, or sexual orientation precludes intercourse with a male partner

    13. 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)

    14. 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.

    1. Requirement for daily systemic corticosteroids above 10 mg of prednisone (or equivalent) per day for the past 2 months

    2. Respiratory infection within 1 month of screening

    3. Intubation for asthma in the last 12 months

    4. Use of warfarin, current or last 30 days

    5. 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

    6. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic Scottsdale Scottsdale Arizona United States 85259
    2 University of Arizona Tucson Tucson Arizona United States 85724
    3 University of California Davis Sacramento California United States 95817
    4 University of California San Diego: Airway Research & Clinical Trials Center San Diego California United States 92103
    5 University of California San Diego: La Jolla Altman Clinical Translation Research Institute San Diego California United States 92121
    6 University of California San Francisco San Francisco California United States 94143
    7 Children's Hospital Colorado Aurora Colorado United States 80045
    8 University of Colorado Denver Aurora Colorado United States 80045
    9 National Jewish Health Denver Colorado United States 802006
    10 Yale University New Haven Connecticut United States 06520
    11 University of South Florida Tampa Florida United States 33613
    12 University of Illinois at Chicago Chicago Illinois United States 60608
    13 Ann & Robert H. Lurie Children's Hospital Chicago Illinois United States 60611
    14 Northwestern Universtiy Chicago Illinois United States 60611
    15 Rush University Chicago Illinois United States 60612
    16 University of Chicago Chicago Illinois United States 60637
    17 Riley Hospital for Children Indianapolis Indiana United States 46202
    18 University of Kansas Kansas City Kansas United States 66160
    19 Boston Children's Hospital Boston Massachusetts United States 02115
    20 Brigham and Women's Hospital Boston Massachusetts United States 02115
    21 University of Michigan Ann Arbor Michigan United States 48109
    22 Washington University Saint Louis Missouri United States 63110
    23 Mount Sinai New York New York United States 10029
    24 Columbia University Medical Center New York New York United States 10031
    25 Wake Forest University Winston-Salem North Carolina United States 27104
    26 Cleveland Clinic Cleveland Ohio United States 44106
    27 University Hospitals Rainbow Babies & Children's Hospital Cleveland Ohio United States 44106
    28 Vanderbilt University Nashville Tennessee United States 37232
    29 University of Wisconsin-Madison Madison Wisconsin United States 53792

    Sponsors and Collaborators

    • University of North Carolina, Chapel Hill
    • National Heart, Lung, and Blood Institute (NHLBI)

    Investigators

    • Principal Investigator: Anastasia Ivanova, University of North Carolina, Chapel Hill

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    University of North Carolina, Chapel Hill
    ClinicalTrials.gov Identifier:
    NCT04129931
    Other Study ID Numbers:
    • 19-1681
    • 5U24HL138998-03
    First Posted:
    Oct 17, 2019
    Last Update Posted:
    Aug 10, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Asthma
    Imatinib Mesylate
    Broncho-Vaxom

    Study Results

    No Results Posted as of Aug 10, 2022