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Early Methicillin-resistant Staphylococcus Aureus (MRSA) Therapy in Cystic Fibrosis (CF) (STAR-Too)

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ClinicalTrials.gov Identifier: NCT01349192
Recruitment Status : Terminated (Interim review showed a statistically significant treatment effect and the DMC recommended that the study be stopped with ongoing follow-up of enrolled subjects)
First Posted : May 6, 2011
Results First Posted : May 15, 2017
Last Update Posted : May 15, 2017
Sponsor:
Collaborators:
CF Therapeutics Development Network Coordinating Center
Seattle Children's Hospital
Washington University School of Medicine
University of Washington
University of Colorado, Denver
Baylor College of Medicine
University of Alabama at Birmingham
Cook Children's Medical Center
University of Michigan
University of Florida
University of Texas Southwestern Medical Center
Children's Hospital Medical Center, Cincinnati
St. Louis Children's Hospital
Information provided by (Responsible Party):
Marianne Muhlebach, MD, University of North Carolina, Chapel Hill

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Investigator);   Primary Purpose: Treatment
Conditions Cystic Fibrosis
Methicillin-resistant Staphylococcus Aureus
Interventions Drug: Rifampin
Drug: Trimethoprim/Sulfamethoxazole
Drug: Minocycline
Drug: Mupirocin
Drug: chlorhexidine gluconate oral rinse
Drug: 2% Chlorhexidine solution wipes
Behavioral: Environmental Decontamination
Enrollment 47

Recruitment Details The trial was conducted from April 1, 2011 to September 2014 at 14 CF Foundation accredited care centers in the United States.
Pre-assignment Details  
Arm/Group Title Treatment Observational
Hide Arm/Group Description

Oral antibiotics:

  1. Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.
  2. Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days.

Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days.

Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist.
Period Title: Overall Study
Started 24 23
Evaluable for Primary Endpoint 22 19
Withdrawals 3 6
Completed 21 17
Not Completed 3 6
Reason Not Completed
Protocol Violation             0             1
Withdrawal by Subject             0             2
Lost to Follow-up             1             3
Failure to adhere to Protocol             2             0
Arm/Group Title Treatment Observational Total
Hide Arm/Group Description

Oral antibiotics:

  1. Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.
  2. Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days.

Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days.

Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist. Total of all reporting groups
Overall Number of Baseline Participants 24 21 45
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants 21 participants 45 participants
12.3  (6.6) 10.5  (5.5) 11.5  (6.1)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age Category Number Analyzed 24 participants 21 participants 45 participants
>=4 and <12 years
13
  54.2%
15
  71.4%
28
  62.2%
>=12 and <18 years
6
  25.0%
5
  23.8%
11
  24.4%
>18 years
5
  20.8%
1
   4.8%
6
  13.3%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 21 participants 45 participants
Female
10
  41.7%
10
  47.6%
20
  44.4%
Male
14
  58.3%
11
  52.4%
25
  55.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race/Ethnicity Combined Number Analyzed 24 participants 21 participants 45 participants
Caucasian
19
  79.2%
17
  81.0%
36
  80.0%
Hispanic
3
  12.5%
2
   9.5%
5
  11.1%
African-American
1
   4.2%
1
   4.8%
2
   4.4%
Other
1
   4.2%
1
   4.8%
2
   4.4%
CF Genotype  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 21 participants 45 participants
Delta F508 Homozygous
6
  25.0%
12
  57.1%
18
  40.0%
Delta F508 Heterozygous
14
  58.3%
7
  33.3%
21
  46.7%
Other
4
  16.7%
2
   9.5%
6
  13.3%
Unidentified
0
   0.0%
0
   0.0%
0
   0.0%
FEV1 Percent of Predicted   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Percent
Number Analyzed 20 participants 17 participants 37 participants
98.5  (21.6) 101.2  (11.8) 99.8  (17.6)
[1]
Measure Description: Percent of predicted forced expiratory volume in one second, based on Wang and Hankinson reference equations.
[2]
Measure Analysis Population Description: Lung function was assessed for the subset of participants that were ≥ 6 years old and able to reliably perform spirometry.
FEV1 Percent of Predicted Category   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 20 participants 17 participants 37 participants
>=30% to <=50%
1
   5.0%
0
   0.0%
1
   2.7%
>50% to <=75%
1
   5.0%
0
   0.0%
1
   2.7%
>75% to <=100%
7
  35.0%
5
  29.4%
12
  32.4%
>100%
11
  55.0%
12
  70.6%
23
  62.2%
[1]
Measure Analysis Population Description: Lung function was assessed for the subset of participants that were ≥ 6 years old and able to reliably perform spirometry.
1.Primary Outcome
Title MRSA Culture Status
Hide Description Proportion of subjects with a negative culture for MRSA at Day 28.
Time Frame Day 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis population is defined as all of the participants who were randomized to a study arm and were assessed for the primary microbiologic efficacy endpoint at both baseline and Day 28.
Arm/Group Title Treatment Observation
Hide Arm/Group Description:

Oral antibiotics:

Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.

Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days. Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days. Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist.
Overall Number of Participants Analyzed 22 19
Measure Type: Count of Participants
Unit of Measure: Participants
18
  81.8%
5
  26.3%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment, Observation
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0005
Comments The a priori threshold for statistical significance was 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion Difference (Final Values)
Estimated Value 0.56
Confidence Interval (2-Sided) 95%
0.25 to 0.74
Estimation Comments Proportion difference was calculated as proportion negative for MRSA in the treatment group minus the proportion negative for MRSA in the observation group. 95% CI calculated using the Newcombe-Wilson method without continuity correction.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment, Observation
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments Test includes adjustment for two interim reviews of efficacy data. The a priori threshold for statistical significance was 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion Difference (Final Values)
Estimated Value 0.525
Confidence Interval (2-Sided) 95%
0.23 to 0.80
Estimation Comments Proportion difference was calculated as proportion negative for MRSA in the treatment group minus the proportion negative for MRSA in the observation group.
2.Secondary Outcome
Title Antibiotic Use (Proportion of Subjects)
Hide Description Proportion of subjects treated with oral, inhaled, and IV antibiotics over the 6 month study.
Time Frame 6 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat
Arm/Group Title Treatment Observation
Hide Arm/Group Description:

Oral antibiotics:

Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.

Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days. Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days. Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist.
Overall Number of Participants Analyzed 24 21
Measure Type: Count of Participants
Unit of Measure: Participants
17
  70.8%
13
  61.9%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment, Observation
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5463
Comments The a priori threshold for statistical significance was 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion Difference (Final Values)
Estimated Value 0.09
Confidence Interval (2-Sided) 95%
-0.18 to 0.34
Estimation Comments Proportion difference was calculated as proportion using antibiotics in the treatment group minus the proportion using antibiotics in the observation group. 95% CI calculated using the Newcombe-Wilson method without continuity correction.
3.Secondary Outcome
Title Antibiotic Use (Days of Use Per Subject)
Hide Description Days of use of oral, inhaled, and IV antibiotics over the 6 month study.
Time Frame 6 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat
Arm/Group Title Treatment Observational
Hide Arm/Group Description:

Oral antibiotics:

  1. Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.
  2. Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days.

Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days.

Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist.
Overall Number of Participants Analyzed 24 21
Mean (Standard Deviation)
Unit of Measure: days
21.9  (23.7) 31.3  (44.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment, Observational
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3683
Comments The a priori threshold for statistical significance was 0.05.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.42
Confidence Interval (2-Sided) 95%
-30.3 to 11.47
Estimation Comments Mean difference was calculated as mean days of antibiotic use in the treatment group minus the mean days of antibiotic use in the observation group.
4.Secondary Outcome
Title Pulmonary Exacerbations
Hide Description Proportion of subjects with a protocol-defined pulmonary exacerbation (PE) between baseline and day 28 who are treated with antibiotics active against MRSA.
Time Frame 28 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat
Arm/Group Title Treatment Observation
Hide Arm/Group Description:

Oral antibiotics:

Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.

Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days. Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days. Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist.
Overall Number of Participants Analyzed 24 21
Measure Type: Count of Participants
Unit of Measure: Participants
2
   8.3%
6
  28.6%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment, Observation
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1205
Comments The a priori threshold for statistical significance was 0.05.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion Difference (Final Values)
Estimated Value -0.20
Confidence Interval (2-Sided) 95%
-0.42 to 0.03
Estimation Comments Difference was calculated as proportion with a PE treated with MRSA active antibiotics in the treatment group minus the analogous proportion in the observation group. 95% CI calculated using the Newcombe-Wilson method without continuity correction.
Time Frame 28 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Treatment Observation
Hide Arm/Group Description

Oral antibiotics:

Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: <40kg : 15mg/kg daily for 14 days divided every 12 hours.

Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.

Pediatric Dose: <40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.

Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.

Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: < 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.

Topical:

Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days. Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days. Environmental disinfection of high use areas

Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist.
All-Cause Mortality
Treatment Observation
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Treatment Observation
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/24 (4.17%)      1/21 (4.76%)    
Infections and infestations     
Cellulitis * 1  1/24 (4.17%)  1 0/21 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Cough * 1  0/24 (0.00%)  0 1/21 (4.76%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Treatment Observation
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   19/24 (79.17%)      13/21 (61.90%)    
Gastrointestinal disorders     
Diarrhoea * 1  4/24 (16.67%)  4 0/21 (0.00%)  0
Nausea * 1  6/24 (25.00%)  7 2/21 (9.52%)  2
Vomiting * 1  5/24 (20.83%)  8 1/21 (4.76%)  1
General disorders     
Pyrexia * 1  3/24 (12.50%)  3 1/21 (4.76%)  3
Investigations     
Weight decreased * 1  0/24 (0.00%)  0 2/21 (9.52%)  2
Metabolism and nutrition disorders     
Decreased appetite * 1  1/24 (4.17%)  1 2/21 (9.52%)  2
Nervous system disorders     
Headache * 1  2/24 (8.33%)  2 0/21 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Cough * 1  10/24 (41.67%)  10 9/21 (42.86%)  10
Nasal congestion * 1  2/24 (8.33%)  3 1/21 (4.76%)  1
Oropharyngeal pain * 1  3/24 (12.50%)  3 1/21 (4.76%)  1
Rhinorrhoea * 1  1/24 (4.17%)  1 3/21 (14.29%)  3
Sputum increased * 1  2/24 (8.33%)  2 1/21 (4.76%)  1
Skin and subcutaneous tissue disorders     
Rash * 1  3/24 (12.50%)  3 0/21 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.0)
The study was completed prior to reaching the pre-specified number of participants as the Data Safety Monitoring committee observed that efficacy had been reached.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Marianne S. Muhlebach, PI
Organization: University of North Carolina, Chapel Hill
Phone: (1) 919 966 1055
Responsible Party: Marianne Muhlebach, MD, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01349192     History of Changes
Other Study ID Numbers: STAR-too-10K0
First Submitted: May 4, 2011
First Posted: May 6, 2011
Results First Submitted: November 2, 2016
Results First Posted: May 15, 2017
Last Update Posted: May 15, 2017