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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04129931
Recruitment Status : Active, not recruiting
First Posted : October 17, 2019
Last Update Posted : April 20, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE October 15, 2019
First Posted Date  ICMJE October 17, 2019
Last Update Posted Date April 20, 2020
Actual Study Start Date  ICMJE December 19, 2019
Estimated Primary Completion Date June 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 15, 2019)
  • Forced Expiratory Volume in one second (FEV1) percent predicted [ Time Frame: 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) [ Time Frame: 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.
  • CompEx events [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2019)
  • Forced Vital Capacity (FVC) pre-bronchodilation [ Time Frame: Measured at 16 weeks after the start of treatment. ]
    Assessed prior to bronchodilator administration
  • FEV1 post-bronchodilation [ Time Frame: Measured at 16 weeks after the start of treatment. ]
    Assessed after bronchodilator administration.
  • Time to first exacerbation [ Time Frame: Assessed over 16 weeks of treatment ]
  • Symptom free days [ Time Frame: Assessed over 16 weeks of treatment ]
  • Asthma free days [ Time Frame: Assessed over 16 weeks of treatment ]
  • Healthcare utilization [ Time Frame: Assessed over 16 weeks of treatment ]
    Asthma-specific Emergency Department visits, asthma-specific hospital admissions, and asthma-specific ICU admissions.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study
Official Title  ICMJE PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study
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 800 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, as well as sites in Canada and the United Kingdom, are involved in PrecISE.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Drug: MCT
    Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily
    Other Name: Breathe Better Diet (BBD)
  • 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
  • Drug: Broncho-Vaxom
    7 mg taken orally once a day, on an empty stomach, for 16 weeks
    Other Name: OM-85 BV VEGETAL
  • 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:
    • Gleevac
    • Zoleta
    • Glivec
    • Ziatir
  • Drug: Cavosonstat
    50 mg capsule orally twice a day for 16 weeks.
    Other Name: N91115
  • Drug: a JAK inhibitor
    Daily for 16 weeks
  • 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.

    The JAK inhibitor Matching Placebo: Daily for 16 weeks.

Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: MCT
    • Other: Placebo
  • 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.
    Interventions:
    • Drug: Clazakizumab
    • Other: Placebo
  • 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.
    Interventions:
    • Drug: Broncho-Vaxom
    • Other: Placebo
  • 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.
    Interventions:
    • Drug: Imatinib Mesylate
    • Other: Placebo
  • 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.
    Interventions:
    • Drug: Cavosonstat
    • Other: Placebo
  • Experimental: a JAK inhibitor
    Participants randomized to this arm will take a JAK inhibitor 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 drug or the matching placebo first or vice versa.
    Interventions:
    • Drug: a JAK inhibitor
    • Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 15, 2019)
800
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04129931
Other Study ID Numbers  ICMJE 19-1681
5U24HL138998-03 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Anastasia Ivanova University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP