Standardized Treatment of Pulmonary Exacerbations II

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Standardized Treatment of Pulmonary Exacerbations II (STOP2)

Conditions
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Pulmonary Cystic Fibrosis

Intervention / Treatment
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* Drug: Standard of care IV antibiotic(s)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: ERR-10<br>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)<br>* IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.<br>|
| Other: ERR-14<br>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)<br>* IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.<br>|
| Other: NERR-14<br>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)<br>* IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.<br>|
| Other: NERR-21<br>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)<br>* IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic fibrosis, Pulmonary exacerbation, Antibiotic, Treatment duration, Lung infection, Cystic Fibrosis Foundation, Cystic Fibrosis Foundation National Patient Registry