Standardized Treatment of Pulmonary Exacerbations II (STOP2)

Standardized Treatment of Pulmonary Exacerbations II (STOP2)

Cystic fibrosis (CF), a life-shortening genetic disease, is marked by acute episodes during which symptoms of lung infection increase and lung function decreases. These pulmonary exacerbations are treated with varying antibiotics for varying time periods based on needs determined by individual patients, their families, and the health care providers. Cystic fibrosis pulmonary guidelines for the treatment of pulmonary exacerbation published by the Cystic Fibrosis Foundation (CFF) in 2009 provided recommendations for treatment and also identified key questions for which additional studies were needed.

A strong desire among clinicians to reduce treatment durations (and reduce cost, inconvenience, and potential toxicities) is in conflict with belief that patients not responding robustly to treatment might benefit from extending treatment.

This randomized, controlled, open-label study is designed to evaluate the efficacy and safety of differing durations of IV treatment, given in the hospital or at home for a pulmonary exacerbation in adult patients with CF.

Study Overview

• Status: Completed
• Conditions: Pulmonary Cystic Fibrosis
• Intervention / Treatment: Drug: Standard of care IV antibiotic(s)

Detailed Description

The study will assess the non-inferiority of 10 days versus 14 days treatment duration among patients who have an early robust improvement (ERR subjects) and the superiority of 21 days versus 14 days treatment duration among the subjects who do not meet the definition of ERR (non-ERR; NERR).

Subjects will undergo pulmonary function testing (spirometry) and complete a respiratory symptom score [Chronic Respiratory Infection Symptom Score (CRISS)] at initiation of IV treatment (Baseline/ Visit 1) and at Day 7-10 (Visit 2). At Visit 2, subjects will be allocated to groups ERR or NERR based on their initial clinical response as determined by the change in forced expiratory volume in 1 second (FEV1; percent of predicted) and CRISS from Baseline and then randomized to an IV treatment duration (nested within group).

ERR subjects [≥8% predicted improvement in FEV1 from Visit 1 to Visit 2 and CRISS reduction of ≥11 points from Visit 1 to Visit 2] will be randomized 1:1 to either 10 days or 14 days total IV antibiotic treatment duration. Remaining (NERR) subjects will be randomized 1:1 to receive either 14 or 21 days total IV antibiotic treatment duration. All subjects will be evaluated again at Visit 3, 14 days following scheduled completion of IV antibiotic treatment.

• Study Type: Interventional
• Enrollment (Actual): 982
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Calgary Canada Adult CF Clinic
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • The Children's Hospital Alabama
  • Alaska
    • Anchorage, Alaska, United States, 99519-6604
      • Providence Alaska Medical Center
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University Medical Center
  • California
    • La Jolla, California, United States, 92037
      • UC San Diego Medical Center
    • Palo Alto, California, United States, 94304
      • Lucile S. Packard Children's Hospital
    • Sacramento, California, United States, 95817
      • University of California Davis, Health System
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Hartford Hospital
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • Shands Hospital
    • Hollywood, Florida, United States, 33021
      • Joe DiMaggio Children's Hospital (Adult)
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Regional Medical Center
  • Illinois
    • Peoria, Illinois, United States, 61603
      • Saint Francis Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital, Indiana University Health
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • John Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital (BCH)
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Health Care (Worcester, MA)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5212
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Detroit Medical Center; Harper University Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Washington University Adult - Barnes-Jewish Hospital
  • Montana
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Long Branch, New Jersey, United States, 07740
      • Monmouth Medical Center
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Robert Wood Johnson University Hospital (New Brunswick, NJ)
  • New York
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • New Hyde Park, New York, United States, 11040
      • The Long Island Jewish Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • Rochester, New York, United States, 14642
      • Highland Hospital; Strong Memorial Hospital
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • North Carolina Children's Hospital
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cleveland, Ohio, United States, 44106
      • University Hospital of Cleveland
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina; Medical University of South Carolina Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • Baylor St. Lukes Medical Center
    • Tyler, Texas, United States, 75708-3154
      • University of Texas Health Center at Tyler
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont Medical Center Inc.
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Richmond, Virginia, United States, 23298
      • Medical College of Virginia (Richmond, VA)
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Ruby Memorial Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital Center
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Key Inclusion Criteria:

• Male or female ≥18 years of age at Visit 1
• Documentation of a CF diagnosis
• Enrolled in the Cystic Fibrosis Foundation National Patient Registry (CFFNPR) prior to Visit 1 (US sites only)
• At the time of Visit 1, there is a plan to initiate IV antibiotics for a pulmonary exacerbation
• Performed spirometry at Visit 1 and Visit 2 and willing to perform spirometry at Visit 3
• Completed the CRISS questionnaire at Visit 1 and Visit 2 and willing to complete the Cystic Fibrosis Respiratory Symptoms Diary (CFRSD) questionnaire at Visit 3
• Willing to adhere to a specific treatment duration determined by initial response to treatment and subsequent randomization
• Willing to return for follow up Visit 3
• Written informed consent obtained from the subject or subject's legal representative

Exclusion Criteria:

Key Exclusion Criteria

• Previous randomization in this study
• Treatment with IV antibiotics in the 6 weeks prior to Visit 1
• Admission to the intensive care unit for current pulmonary exacerbation in the two weeks prior to Visit 2, unless admission was due to a desensitization protocol
• Pneumothorax in the two weeks prior to Visit 2
• Primary diagnosis for current hospitalization is unrelated to worsening lower respiratory symptoms (e.g., pulmonary clean out, distal intestinal obstruction syndrome (DIOS), sinusitis)
• Massive hemoptysis defined as > 250 cc in a 24 hour period or 100 cc/day over 4 consecutive days occurring in the two weeks prior to Visit 2
• Current pulmonary exacerbation thought to be due to allergic bronchopulmonary aspergillosis (ABPA)
• At Visit 1, receiving ongoing treatment with a duration of more than 2 weeks with prednisone equivalent to >10mg/day
• History of solid organ transplantation
• Receiving antimicrobial therapy to treat non-tuberculous mycobacterium (e.g., M. abscessus, M. avium complex) in the two weeks prior to Visit 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: ERR-10; ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Other: ERR-14; ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Other: NERR-14; NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Other: NERR-21; NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day	Absolute change in FEV1 % predicted from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).	Start of IV antibiotic treatment to 14 days after the end of IV antibiotic treatment
Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21	Absolute change in FEV1 % predicted from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CRISS From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day	Absolute change in respiratory symptoms, as measured by the the Cystic Fibrosis Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment). The Diary asks a participant to state the extent of their 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Change in CRISS From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day	Absolute change in respiratory symptoms, as measured by the the Cystic Fibrosis Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment). The Diary asks a participant to state the extent of their 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Change in Weight From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day	Absolute change in weight (kg) from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Change in Weight From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day	Absolute change in weight (kg) from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Collaborators and Investigators

• Sponsor: Chris Goss
• Collaborators: Medical University of South Carolina; University of Washington; Cystic Fibrosis Foundation; CF Therapeutics Development Network Coordinating Center

Publications and helpful links

General Publications

• Gold LS, Hansen RN, Patrick DL, Tabah A, Heltshe SL, Flume PA, Goss CH, West NE, Sanders DB, VanDevanter DR, Kessler L. Health care costs in a randomized trial of antimicrobial duration among cystic fibrosis patients with pulmonary exacerbations. J Cyst Fibros. 2022 Jul;21(4):594-599. doi: 10.1016/j.jcf.2022.03.001. Epub 2022 Mar 14.
• VanDevanter DR, Heltshe SL, Skalland M, West NE, Sanders DB, Goss CH, Flume PA. C-reactive protein (CRP) as a biomarker of pulmonary exacerbation presentation and treatment response. J Cyst Fibros. 2022 Jul;21(4):588-593. doi: 10.1016/j.jcf.2021.12.003. Epub 2021 Dec 18.
• Goss CH, Heltshe SL, West NE, Skalland M, Sanders DB, Jain R, Barto TL, Fogarty B, Marshall BC, VanDevanter DR, Flume PA; STOP2 Investigators. A Randomized Clinical Trial of Antimicrobial Duration for Cystic Fibrosis Pulmonary Exacerbation Treatment. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1295-1305. doi: 10.1164/rccm.202102-0461OC.
• Holland P, Jahnke N. Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis. Cochrane Database Syst Rev. 2021 Jun 23;6(6):CD002007. doi: 10.1002/14651858.CD002007.pub5.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): March 6, 2020
• Study Completion (Actual): March 6, 2020

Study Registration Dates

• First Submitted: May 12, 2016
• First Submitted That Met QC Criteria: May 23, 2016
• First Posted (Estimate): May 24, 2016

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Antibiotic; Pulmonary exacerbation; Treatment duration; Lung infection; Cystic Fibrosis Foundation; Cystic Fibrosis Foundation National Patient Registry
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: STOP2-IP-15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO