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Steroids In Eosinophil Negative Asthma (SIENA)

Primary Purpose

Asthma

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Mometasone 220mcg BID
Tiotropium Respimat 5mcg QD
Placebo
Sponsored by
Milton S. Hershey Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asthma focused on measuring Asthma, Mometasone, Tiotropium

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Physician-diagnosed asthma for at least previous 12 months.
  • Able to perform reproducible spirometry.
  • Baseline FEV1≥70% of predicted.

  • Asthma confirmed either by:

    • Beta-agonist reversibility to 4 puffs albuterol ≥ 12% OR
    • Methacholine PC20 ≤ 16 mg/ml

  • At least 1 of the following indications for chronic controller therapy:

    • Asthma Symptoms > 2 days/week OR
    • Nocturnal Asthma Symptoms > 2 nights/month OR
    • Short-acting beta-agonist use for symptom control > 2 days/week
  • For participants ≥18 years of age: Ability to provide informed consent. For participants under 18 years of age: Ability to provide verbal or written assent and ability of parent to provide informed consent.
  • Willingness, if female and able to conceive, to utilize one medically-acceptable form of contraception.

Exclusion Criteria:

  • Chronic inhaled or oral corticosteroid therapy.
  • Use of inhaled or oral corticosteroid therapy within 6 weeks.
  • New allergen immunotherapy within the past 3 months or anticipated changes to an ongoing immunotherapy regimen.
  • Use of omalizumab within 3 months.

  • History of:

    • bladder-neck obstruction, urinary retention or benign prostatic hyperplasia
    • narrow angle glaucoma
    • significant cardiovascular disorders and arrhythmias
    • life-threatening asthma requiring treatment with intubation or mechanical ventilation within the past 5 years
  • Respiratory tract infection within past 6 weeks.
  • History of smoking within the past 1 year, or > 10 pack-years total if ≥ 18 years of age, or > 5 pack-years total if < 18 years of age.
  • Chronic diseases or medical conditions (other than asthma) that could put the participant at risk by participation, e.g. chronic diseases of the lung (other than asthma), heart, liver, kidney, endocrine or nervous system, or immunodeficiency.

Sites / Locations

  • University of Arizona College of Medicine
  • UCSF Benioff Children's Hospital
  • University of California at San Francisco
  • National Jewish Health
  • Nemours Children's Clinic
  • Nemours Children's Clinic
  • Emory University
  • Northwestern Memorial Hospital
  • Rush University Medical Center
  • University of Illinois at Chicago
  • Ann and Robert H. Lurie Children's Hospital
  • University of Chicago
  • Brigham and Women's Hospital
  • Children's Hospital Boston
  • St. Louis Children's Hospital
  • Washington University
  • Columbia University Medical Center
  • Duke University School of Medicine
  • North Carolina Clinical Research
  • Wake Forest University Health Sciences
  • Rainbow Babies and Children's Hospital, Case Western Reserve University
  • Allegheny General Hospital
  • University of Pittsburgh
  • Children's Hospital of Pittsburgh of UPMC
  • University of Wisconsin-Madison

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Mometasone then Tiotropium then Placebo

Mometasone then Placebo then Tiotropium

Placebo then Mometasone then Tiotropium

Placebo then Tiotropium then Mometasone

Tiotropium then Placebo then Mometasone

Tiotropium then Mometasone then Placebo

Arm Description

Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo

Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD

Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD

Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID

Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID

Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo

Outcomes

Primary Outcome Measures

Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1.
This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response.

Secondary Outcome Measures

Treatment Failure
Treatment Failure includes: Awakening from asthma three or more times in a two-week period or on two consecutive nights, or Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or exercise induces unusual breathlessness
Annualized Asthma Control Days
Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF < 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365.
Forced Expiratory Volume at One Second (FEV1) Percent of Predicted
FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height.
Peak Expiratory Flow Rate
Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways.
Asthma Exacerbations
Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: FEV1 <50% of baseline on 2 consecutive measurements FEV1 <40% of predicted on 2 consecutive measurements Use of ≥ 16 puffs of "as needed" β-agonist per 24 hours for a period of 48 hours Use of oral/parenteral corticosteroid due to asthma

Full Information

First Posted
February 10, 2014
Last Updated
May 16, 2019
Sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02066298
Brief Title
Steroids In Eosinophil Negative Asthma
Acronym
SIENA
Official Title
Steroids In Eosinophil Negative Asthma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
July 2014 (Actual)
Primary Completion Date
May 2018 (Actual)
Study Completion Date
May 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Because approximately half of all mild-moderately-severe asthma is persistently non-eosinophilic, it is important to determine prospectively if patients who are persistently non-eosinophilic differ in their benefit from inhaled corticosteroid treatment compared to patients who are not persistently non-eosinophilic.
Detailed Description
SIENA is a 42-week randomized, stratified, 3-period double-blind placebo-controlled crossover study of patients with symptomatic mild-to-moderate asthma, not already taking an inhaled corticosteroid, in whom the effect of "medium-dose" inhaled corticosteroid (ICS) will be compared with the effect of placebo and with a long-acting muscarinic antagonist (LMA).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma
Keywords
Asthma, Mometasone, Tiotropium

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
295 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mometasone then Tiotropium then Placebo
Arm Type
Experimental
Arm Description
Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo
Arm Title
Mometasone then Placebo then Tiotropium
Arm Type
Experimental
Arm Description
Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD
Arm Title
Placebo then Mometasone then Tiotropium
Arm Type
Experimental
Arm Description
Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD
Arm Title
Placebo then Tiotropium then Mometasone
Arm Type
Experimental
Arm Description
Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID
Arm Title
Tiotropium then Placebo then Mometasone
Arm Type
Experimental
Arm Description
Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID
Arm Title
Tiotropium then Mometasone then Placebo
Arm Type
Experimental
Arm Description
Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo
Intervention Type
Drug
Intervention Name(s)
Mometasone 220mcg BID
Other Intervention Name(s)
Asmanex
Intervention Description
Mometasone is an ICS
Intervention Type
Drug
Intervention Name(s)
Tiotropium Respimat 5mcg QD
Intervention Description
Tiotropium is a LMA
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1.
Description
This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response.
Time Frame
End of 12-week treatment period
Secondary Outcome Measure Information:
Title
Treatment Failure
Description
Treatment Failure includes: Awakening from asthma three or more times in a two-week period or on two consecutive nights, or Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or exercise induces unusual breathlessness
Time Frame
End of 12-week treatment period
Title
Annualized Asthma Control Days
Description
Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF < 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365.
Time Frame
End of 12-week treatment period
Title
Forced Expiratory Volume at One Second (FEV1) Percent of Predicted
Description
FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height.
Time Frame
End of 12-week treatment period
Title
Peak Expiratory Flow Rate
Description
Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways.
Time Frame
End of 12-week treatment period
Title
Asthma Exacerbations
Description
Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: FEV1 <50% of baseline on 2 consecutive measurements FEV1 <40% of predicted on 2 consecutive measurements Use of ≥ 16 puffs of "as needed" β-agonist per 24 hours for a period of 48 hours Use of oral/parenteral corticosteroid due to asthma
Time Frame
End of 12-week treatment period

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Physician-diagnosed asthma for at least previous 12 months. Able to perform reproducible spirometry. Baseline FEV1≥70% of predicted. Asthma confirmed either by: Beta-agonist reversibility to 4 puffs albuterol ≥ 12% OR Methacholine PC20 ≤ 16 mg/ml At least 1 of the following indications for chronic controller therapy: Asthma Symptoms > 2 days/week OR Nocturnal Asthma Symptoms > 2 nights/month OR Short-acting beta-agonist use for symptom control > 2 days/week For participants ≥18 years of age: Ability to provide informed consent. For participants under 18 years of age: Ability to provide verbal or written assent and ability of parent to provide informed consent. Willingness, if female and able to conceive, to utilize one medically-acceptable form of contraception. Exclusion Criteria: Chronic inhaled or oral corticosteroid therapy. Use of inhaled or oral corticosteroid therapy within 6 weeks. New allergen immunotherapy within the past 3 months or anticipated changes to an ongoing immunotherapy regimen. Use of omalizumab within 3 months. History of: bladder-neck obstruction, urinary retention or benign prostatic hyperplasia narrow angle glaucoma significant cardiovascular disorders and arrhythmias life-threatening asthma requiring treatment with intubation or mechanical ventilation within the past 5 years Respiratory tract infection within past 6 weeks. History of smoking within the past 1 year, or > 10 pack-years total if ≥ 18 years of age, or > 5 pack-years total if < 18 years of age. Chronic diseases or medical conditions (other than asthma) that could put the participant at risk by participation, e.g. chronic diseases of the lung (other than asthma), heart, liver, kidney, endocrine or nervous system, or immunodeficiency.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William Busse, M.D.
Organizational Affiliation
University of Wisconsin, Madison
Official's Role
Study Chair
Facility Information:
Facility Name
University of Arizona College of Medicine
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
UCSF Benioff Children's Hospital
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
University of California at San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
National Jewish Health
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
Nemours Children's Clinic
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
Country
United States
Facility Name
Nemours Children's Clinic
City
Orlando
State/Province
Florida
ZIP/Postal Code
32827
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Ann and Robert H. Lurie Children's Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Children's Hospital Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
St. Louis Children's Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Duke University School of Medicine
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27110
Country
United States
Facility Name
North Carolina Clinical Research
City
Raleigh
State/Province
North Carolina
ZIP/Postal Code
27607
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Rainbow Babies and Children's Hospital, Case Western Reserve University
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Allegheny General Hospital
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15212
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
University of Wisconsin-Madison
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
31112384
Citation
Lazarus SC, Krishnan JA, King TS, Lang JE, Blake KV, Covar R, Lugogo N, Wenzel S, Chinchilli VM, Mauger DT, Dyer AM, Boushey HA, Fahy JV, Woodruff PG, Bacharier LB, Cabana MD, Cardet JC, Castro M, Chmiel J, Denlinger L, DiMango E, Fitzpatrick AM, Gentile D, Hastie A, Holguin F, Israel E, Jackson D, Kraft M, LaForce C, Lemanske RF Jr, Martinez FD, Moore W, Morgan WJ, Moy JN, Myers R, Peters SP, Phipatanakul W, Pongracic JA, Que L, Ross K, Smith L, Szefler SJ, Wechsler ME, Sorkness CA; National Heart, Lung, and Blood Institute AsthmaNet. Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level. N Engl J Med. 2019 May 23;380(21):2009-2019. doi: 10.1056/NEJMoa1814917. Epub 2019 May 19.
Results Reference
derived
PubMed Identifier
30593883
Citation
Sorkness CA, King TS, Dyer AM, Chinchilli VM, Mauger DT, Krishnan JA, Blake K, Castro M, Covar R, Israel E, Kraft M, Lang JE, Lugogo N, Peters SP, Wechsler ME, Wenzel SE, Lazarus SC; National Heart Lung and Blood Institute's "AsthmaNet". Adapting clinical trial design to maintain meaningful outcomes during a multicenter asthma trial in the precision medicine era. Contemp Clin Trials. 2019 Feb;77:98-103. doi: 10.1016/j.cct.2018.12.012. Epub 2018 Dec 27.
Results Reference
derived
Links:
URL
http://asthmanetresearch.org/
Description
AsthmaNet

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Steroids In Eosinophil Negative Asthma

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