Pulmonary Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis, Pulmonary exacerbation, Antibiotic, Treatment duration, Lung infection, Cystic Fibrosis Foundation, Cystic Fibrosis Foundation National Patient Registry
Brief summary
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
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.
Interventions
DRUGStandard 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.
Sponsors
Cystic Fibrosis Foundation
CF Therapeutics Development Network Coordinating Center
Medical University of South Carolina
University of Washington
Chris Goss
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | Start of IV antibiotic treatment to 14 days after the end of IV antibiotic treatment | 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). |
| Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 | Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CRISS From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment | 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. |
| Change in CRISS From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day | Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment | 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. |
| Change in Weight From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment | 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). |
| Change in Weight From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day | Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment | 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). |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 107 |
| 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.
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. | 107 |
| 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.
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. | 353 |
| 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.
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. | 352 |
| Total | 919 |
Baseline characteristics
| Characteristic | Total | ERR-10 | ERR-14 | NERR-14 | NERR-21 |
|---|---|---|---|---|---|
| Age, Continuous | 30.6 years STANDARD_DEVIATION 9.79 | 26.6 years STANDARD_DEVIATION 6.34 | 27.1 years STANDARD_DEVIATION 8.89 | 31.8 years STANDARD_DEVIATION 10.52 | 31.5 years STANDARD_DEVIATION 9.63 |
| Cystic Fibrosis (CF) Genotype Delta F508 Heterozygous | 347 Participants | 45 Participants | 40 Participants | 127 Participants | 135 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Homozygous | 446 Participants | 46 Participants | 55 Participants | 171 Participants | 174 Participants |
| Cystic Fibrosis (CF) Genotype Other/Unknown | 126 Participants | 16 Participants | 12 Participants | 55 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 63 Participants | 8 Participants | 9 Participants | 26 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 856 Participants | 99 Participants | 98 Participants | 327 Participants | 332 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| FEV1 (% Predicted) Distribution <50% | 507 Participants | 60 Participants | 61 Participants | 192 Participants | 194 Participants |
| FEV1 (% Predicted) Distribution >=50% | 412 Participants | 47 Participants | 46 Participants | 161 Participants | 158 Participants |
| Forced Expiratory Volume in 1 second (FEV1) | 1.8 liters STANDARD_DEVIATION 0.8 | 1.9 liters STANDARD_DEVIATION 0.8 | 1.8 liters STANDARD_DEVIATION 0.83 | 1.8 liters STANDARD_DEVIATION 0.83 | 1.8 liters STANDARD_DEVIATION 0.76 |
| History of PEx in last year 0 - 1 | 377 Participants | 43 Participants | 45 Participants | 145 Participants | 144 Participants |
| History of PEx in last year >=2 | 542 Participants | 64 Participants | 62 Participants | 208 Participants | 208 Participants |
| IV Antibiotic Treatment Location Prior to Randomization All at Home | 206 Participants | 15 Participants | 17 Participants | 88 Participants | 86 Participants |
| IV Antibiotic Treatment Location Prior to Randomization Any Nights in Hospital | 713 Participants | 92 Participants | 90 Participants | 265 Participants | 266 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants | 5 Participants | 3 Participants | 7 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 13 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) White | 855 Participants | 98 Participants | 100 Participants | 335 Participants | 322 Participants |
| Sex: Female, Male Female | 462 Participants | 46 Participants | 53 Participants | 192 Participants | 171 Participants |
| Sex: Female, Male Male | 457 Participants | 61 Participants | 54 Participants | 161 Participants | 181 Participants |
| Systemic Corticosteroid Use No | 832 Participants | 94 Participants | 97 Participants | 330 Participants | 311 Participants |
| Systemic Corticosteroid Use Yes | 87 Participants | 13 Participants | 10 Participants | 23 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 140 | 0 / 137 | 0 / 353 | 0 / 352 |
| other Total, other adverse events | 8 / 140 | 4 / 137 | 4 / 353 | 4 / 352 |
| serious Total, serious adverse events | 4 / 140 | 1 / 137 | 19 / 353 | 19 / 352 |
Outcome results
Primary
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).
Time frame: Start of IV antibiotic treatment to 14 days after the end of IV antibiotic treatment
Population: Includes only participants within the ERR treatment group and per-protocol population, with FEV1 measurements at baseline and last study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ERR-10 | Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | 13.30 percentage change | Standard Deviation 9.65 |
| ERR-14 | Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | 13.83 percentage change | Standard Deviation 9.94 |
Comparison: The ERR non-inferiority test was a priori designed to be conducted on the per-protocol (PP) population for 93% power assuming 2-sided alpha=0.05 with 155 PP participants per arm. Difference between ERR treatment duration arms is ERR-10 - ERR-14.p-value: 0.016495% CI: [-3.3, 2]ANOVA
Primary
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).
Time frame: Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Population: Includes only participants within the NERR treatment group and intent-to-treat population, with FEV1 measurements at baseline and last study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ERR-10 | Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 | 3.60 percentage change | Standard Deviation 8.22 |
| ERR-14 | Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 | 3.53 percentage change | Standard Deviation 7.13 |
Comparison: The NERR superiority test was a priori designed to be conducted on the Intent-to-Treat (ITT) population for 91% power to detect a 2.5% difference, assuming 2-sided alpha=0.05 with 285 ITT participants per arm. Difference between NERR treatment duration arms is NERR-21 - NERR-14.p-value: 0.56895% CI: [-1.3, 1.1]ANOVA
Secondary
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.
Time frame: Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Population: Includes only participants within the ERR treatment group and per-protocol (PP) population, with CRISS measurements at baseline and last study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ERR-10 | Change in CRISS From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | -24.2 score on a scale | Standard Deviation 13.21 |
| ERR-14 | Change in CRISS From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | -25.3 score on a scale | Standard Deviation 12.89 |
Comparison: Difference between ERR treatment duration arms is ERR-10 - ERR-14.p-value: 0.54695% CI: [-2.4, 4.6]t-test, 2 sided
Secondary
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.
Time frame: Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Population: Includes only participants within the NERR treatment group and intent-to-treat (ITT) population, with CRISS measurements at baseline and last study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ERR-10 | Change in CRISS From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day | -15.1 score on a scale | Standard Deviation 13.74 |
| ERR-14 | Change in CRISS From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day | -16.7 score on a scale | Standard Deviation 14.15 |
Comparison: Difference between NERR treatment duration arms is NERR-21 - NERR-14.p-value: 0.1495% CI: [-3.7, 0.5]t-test, 2 sided
Secondary
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).
Time frame: Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Population: Includes only participants within the ERR treatment group and per-protocol (PP) population, with weight measurements at baseline and last study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ERR-10 | Change in Weight From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | 1.7 kg | Standard Deviation 2.18 |
| ERR-14 | Change in Weight From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day | 1.5 kg | Standard Deviation 2.21 |
Comparison: Difference between ERR treatment duration arms is ERR-10 - ERR-14.p-value: 0.56395% CI: [-0.42, 0.77]t-test, 2 sided
Secondary
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).
Time frame: Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment
Population: Includes only participants within the NERR treatment group and intent-to-treat (ITT) population, with weight measurements at baseline and last study visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ERR-10 | Change in Weight From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day | 0.5 kg | Standard Deviation 2.16 |
| ERR-14 | Change in Weight From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day | 0.8 kg | Standard Deviation 2.07 |
p-value: 0.08395% CI: [-0.04, 0.61]t-test, 2 sided