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Comparison of Two Treatment Regimens to Reduce PA Infection in Children With Cystic Fibrosis (EPIC)

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Cystic Fibrosis Foundation Therapeutics
CF Therapeutics Development Network Coordinating Center
Information provided by (Responsible Party):
Bonnie Ramsey, Seattle Children's Hospital
ClinicalTrials.gov Identifier:
NCT00097773
First received: November 30, 2004
Last updated: January 28, 2014
Last verified: January 2014
Results First Received: June 11, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions: Cystic Fibrosis
Pulmonary Disease, Chronic Obstructive
Interventions: Drug: Tobramycin solution for inhalation (TOBI)
Drug: Oral placebo
Drug: Oral ciprofloxacin

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Recruitment was conducted from December 2004 to June 2009 from 55 Cystic Fibrosis Foundation accredited clinical centers throughout the US

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Cycled TOBI and Oral Placebo Tobramycin solution for inhalation (TOBI) and oral placebo for six consecutive quarterly cycles
Cycled TOBI and Oral Ciprofloxacin Tobramycin solution for inhalation (TOBI) and oral ciprofloxacin for six consecutive quarterly cycles
Culture-Based TOBI and Oral Ciprofloxacin Tobramycin solution for inhalation (TOBI) and oral ciprofloxacin administered only when quarterly respiratory cultures are found positive for Pseudomonas aeruginosa (Pa)
Culture-Based TOBI and Oral Placebo Tobramycin solution for inhalation (TOBI) and oral placebo administered only when quarterly respiratory cultures are found positive for Pseudomonas aeruginosa (Pa)

Participant Flow:   Overall Study
    Cycled TOBI and Oral Placebo   Cycled TOBI and Oral Ciprofloxacin   Culture-Based TOBI and Oral Ciprofloxacin   Culture-Based TOBI and Oral Placebo
STARTED   76   76   76   76 
COMPLETED   68   68   68   73 
NOT COMPLETED   8   8   8   3 
Lost to Follow-up                2                2                0                1 
Physician Decision                2                2                3                1 
Withdrawal by Subject                3                3                3                1 
Adverse Event                0                1                0                0 
Other                1                0                2                0 



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat

Reporting Groups
  Description
Cycled TIS w/Placebo TOBI and oral placebo for six consecutive quarterly cycles
Cycled TIS w/Cipro TOBI and oral ciprofloxacin for six consecutive quarterly cycles
Culture-Based TIS w/Placebo TOBI and oral placebo administered only when quarterly respiratory cultures are found positive for Pseudomonas aeruginosa (Pa)
Culture-Based TIS w/Cipro TOBI and oral ciprofloxacin administered only when quarterly respiratory cultures are found positive for Pseudomonas aeruginosa (Pa)
Total Total of all reporting groups

Baseline Measures
   Cycled TIS w/Placebo   Cycled TIS w/Cipro   Culture-Based TIS w/Placebo   Culture-Based TIS w/Cipro   Total 
Overall Participants Analyzed 
[Units: Participants]
 76   76   76   76   304 
Age 
[Units: Participants]
         
<=18 years   76   76   76   76   304 
Between 18 and 65 years   0   0   0   0   0 
>=65 years   0   0   0   0   0 
Age 
[Units: Years]
Mean (Standard Deviation)
 5.8  (3.43)   5.9  (3.28)   6.0  (3.74)   5.0  (3.58)   5.7  (3.51) 
Gender 
[Units: Participants]
         
Female   45   32   40   37   154 
Male   31   44   36   39   150 
Region of Enrollment 
[Units: Participants]
         
United States   76   76   76   76   304 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization   [ Time Frame: Measured over the 18 month study ]

Measure Type Primary
Measure Title Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization
Measure Description

The primary comparison is between the pooled culture-based group and the pooled cycled group. A secondary comparison is between the pooled ciprofloxacin group vs the pooled placebo group. Descriptive results are provided for the pooled treatment groups.

Participants are represented once in the cycled and culture-based therapy columns, and once in the cipro and placebo columns.

Time Frame Measured over the 18 month study  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat

Reporting Groups
  Description
Cycled TIS Pooled Cycled tobramycin solution for inhalation (TIS) therapy group
Culture-Based TIS Pooled Culture-Based TIS therapy group
Oral Ciprofloxacin Pooled oral cipro group
Oral Placebo Pooled oral placebo group

Measured Values
   Cycled TIS   Culture-Based TIS   Oral Ciprofloxacin   Oral Placebo 
Participants Analyzed 
[Units: Participants]
 152   152   152   152 
Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization 
[Units: Number of participants]
 24   26   29   21 


Statistical Analysis 1 for Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization
Groups [1] Cycled TIS vs. Culture-Based TIS
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Cox
P Value [4] 0.86
Hazard Ratio (HR) [5] 0.95
95% Confidence Interval 0.54 to 1.66
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The primary analysis compared the pooled Cycled Therapy group (n=152) vs. the Pooled culture-based therapy group (n=152). The null hypothesis was no difference between groups in the risk of pulmonary exacerbation requiring IV antibiotics or hospitalization. Assuming a total sample size of 300 (150 per group), the study provided 80% power to detect at least a 40% reduction in the risk of exacerbation in the cycled group as compared to the culture-based group at the two-sided alpha level of 5%.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  There was no significant interaction with ciprofloxacin in this analysis.
[5] Other relevant estimation information:
  risk of exacerbation comparing cycled therapy to culture-based therapy

Statistical Analysis 2 for Number of Participants With a Pulmonary Exacerbation Requiring IV Antibiotics or Hospitalization
Groups [1] Oral Ciprofloxacin vs. Oral Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Cox
P Value [4] 0.20
Hazard Ratio (HR) [5] 1.45
95% Confidence Interval 0.82 to 2.54
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  A secondary comparison was between the pooled oral cipro (n=152)and pooled placebo groups (n=152. Null hypothesis was no difference between groups.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  risk of exacerbation comparing oral cipro to oral placebo



2.  Secondary:   Proportion of Participants With a Pa Positive Culture   [ Time Frame: Week 10 (after initial treatment course for Pa) through Month 18 ]

Measure Type Secondary
Measure Title Proportion of Participants With a Pa Positive Culture
Measure Description

Proportion of participants with a Pa positive culture compared between (1) the pooled cycled therapy group (n=152) and pooled culture-based therapy group (n=152), and (2) between the pooled oral placebo (n=152)and pooled cipro groups (n=152).

Participants are included once in the cycled and culture-based columns, and once in the oral cipro and placebo columns

Time Frame Week 10 (after initial treatment course for Pa) through Month 18  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat

Reporting Groups
  Description
Cycled TIS Pooled Cycled TIS group
Culture-Based TIS Pooled Culture-Based TIS group
Oral Cipro Pooled oral cipro group
Oral Placebo pooled oral placebo group

Measured Values
   Cycled TIS   Culture-Based TIS   Oral Cipro   Oral Placebo 
Participants Analyzed 
[Units: Participants]
 152   152   152   152 
Proportion of Participants With a Pa Positive Culture 
[Units: Participants]
       
No Pa positive cultures   109   85   97   97 
1 Pa positive culture   17   38   22   33 
2 Pa positive cultures   9   18   13   14 
3 or more Pa positive cultures   13   9   14   8 
Missing   4   2   6   0 


Statistical Analysis 1 for Proportion of Participants With a Pa Positive Culture
Groups [1] Cycled TIS vs. Culture-Based TIS
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.28
Odds Ratio (OR) [5] 0.78
95% Confidence Interval 0.49 to 1.23
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis is that there is no difference between pooled cycled and culture-based treatment groups in the odds of a Pa positive culture over the 18 month study.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No interaction with ciprofloxacin usage was observed.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  odds of a positive culture comparing cycled therapy to culture-based therapy

Statistical Analysis 2 for Proportion of Participants With a Pa Positive Culture
Groups [1] Oral Cipro vs. Oral Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Logistic
P Value [4] 0.67
Odds Ratio (OR) [5] 1.10
95% Confidence Interval 0.71 to 1.71
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Null hypothesis is that there is no difference between pooled cipro and placebo treatment groups in the odds of a Pa positive culture over the 18 month study.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  odds of a positive culture comparing the cipro group to the placebo group



3.  Secondary:   Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics   [ Time Frame: Measured over the 18 month time period ]

Measure Type Secondary
Measure Title Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics
Measure Description

The primary comparison is between the pooled culture-based group and the pooled cycled group. No interactions with ciprofloxacin were identified. A secondary comparison is between the pooled ciprofloxacin group vs the pooled placebo group. Descriptive results are provided for the pooled treatment groups.

Participants are represented once in the cycled and culture-based therapy columns, and once in the cipro and placebo columns.

Time Frame Measured over the 18 month time period  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat

Reporting Groups
  Description
Cycled TIS Pooled Cycled TIS therapy group
Culture-Based TIS Pooled Culture-Based TIS therapy group
Oral Ciprofloxacin Pooled oral cipro group
Oral Placebo Pooled oral placebo group

Measured Values
   Cycled TIS   Culture-Based TIS   Oral Ciprofloxacin   Oral Placebo 
Participants Analyzed 
[Units: Participants]
 152   152   152   152 
Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics 
[Units: Participants]
 70   81   83   68 


Statistical Analysis 1 for Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics
Groups [1] Cycled TIS vs. Culture-Based TIS
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Cox
P Value [4] 0.18
Hazard Ratio (HR) [5] 0.80
95% Confidence Interval 0.58 to 1.11
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis compared the pooled Cycled Therapy group (n=152) vs. the Pooled culture-based therapy group (n=152). The null hypothesis was no difference between groups in the risk of pulmonary exacerbation.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No interaction with ciprofloxacin usage was observed.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  Hazard ratio comparing cycled to culture based therapy

Statistical Analysis 2 for Number of Participants With a Pulmonary Exacerbation Requiring Oral, Inhaled, or Oral Antibiotics
Groups [1] Oral Ciprofloxacin vs. Oral Placebo
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Cox
P Value [4] 0.12
Hazard Ratio (HR) [5] 1.29
95% Confidence Interval 0.94 to 1.78
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  This analysis was between the pooled oral cipro (n=152)and pooled placebo groups (n=152. Null hypothesis was no difference between groups.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  Hazard ratio comparing cipro to placebo.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information