Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis
Brief summary
This study assessed time to recurrence of infection with Pseudomonas aeruginosa following treatment of the initial infection with tobramycin nebuliser solution. The safety profile of the initial tobramycin treatment was assessed during the first 3 months of the study and patients were followed until the end of the study, month 27.
Detailed description
This was a multi-center, open-label, two-arm, randomized study. All patients diagnosed with CF and who fulfilled the criteria for early infection with P. aeruginosa initially received tobramycin 300 mg twice a day for 28 days. At the end of the 28-day treatment period, patients who met the inclusion criteria and none of the additional exclusion criteria were randomized in a 1:1 ratio to either receive an additional 28 days of treatment with tobramycin 300 mg twice a day (56-day group) or to stop study medication (28-day group). All randomized patients had regular study visits until a positive P. aeruginosa sample was obtained. Once P. aeruginosa had recurred, the patient entered a follow-up phase where minimal information was collected for 27 months. During the follow-up phase, patients were treated according to their physicians' discretion. Patients who started treatment with tobramycin but were not randomized (i.e. due to a positive antibody test) and followed up during routine clinic visits. They were allowed to continue their 28-day treatment period and afterwards be treated according to their physicians' discretion.
Interventions
DRUGTobramycin solution for inhalation 300 mg
Tobramycin solution for inhalation was supplied in 5 mL liquid-filled low-density polyethylene ampoules containing 300 mg tobramycin. Patients used a nebulizer to inhale the contents of the ampoules.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥ 6 months old * Diagnosis of cystic fibrosis (CF) based upon the following historical criteria performed prior to study participation: 1. confirmed sweat chloride \> 60 mEq/L by quantitative pilocarpine iontophoresis (at least 2 tests), OR 2. genotype with two identifiable mutations consistent with CF. * First or early lower respiratory tract infection with Pseudomonas (P.) aeruginosa documented by either of the following: 1. first infection defined by the first P. aeruginosa isolated from sputum or deep throat cough swab culture, OR 2. P. aeruginosa from sputum or deep throat cough swab culture following at least 1 year of negative cultures (documented with at least 4 negative cultures during this year and no positive cultures) and no anti-pseudomonal treatment during this 1-year period, OR 3. P. aeruginosa from sputum or deep throat cough swab culture following at least 2 years of negative cultures (documented with at least 2 negative cultures per year and no positive cultures) and no anti-pseudomonal treatment during this 2-year period. * Written informed consent by the patient and/or parent/legal guardian according to local country regulations.
Exclusion criteria
* History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycoside. * Signs and symptoms of acute pulmonary disease, eg, pneumonia, pneumothorax. * Administration of any investigational drug within 30 days prior to enrollment. * Administration of loop diuretics within 7 days prior to study drug administration. * Personal/family history of abnormal hearing, other than typical hearing loss associated with the aging process. * Abnormal result from an audiology testing (defined as either a unilateral pure-tone audiometry test showing a threshold elevation \> 20 decibels \[dB\] at any frequency across the frequency range 0.25-8 kHz or the absence of emission at the evoked otoacoustic emission test). * Positive urine pregnancy test at Day 1 (Baseline) for all female patients who have reached menarche. * Use of macrolide antibiotics as a maintenance therapy for 12 or more days during the 28 days prior to Baseline. * Antibody titers ≥ 1000 for any of the 3 P. aeruginosa exoenzymes: Exotoxin A, alkaline protease, or elastase (status to be determined between Baseline and Day 28).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence of Pseudomonas (P.) Aeruginosa (Any Genotype) in Sputum or Deep Throat Cough Swab | From 1 month after the end of treatment (Day 56 for the 28-day treatment group and Month 3 for the 56-day treatment group) until the end of the study (Month 27) | Microbiological samples were obtained from sputum or by deep throat cough swab technique. Time to recurrence was defined as the time between the visit at 1 month after the end of treatment (when eradication was confirmed) and the time of the first positive culture with any genotype of P. aeruginosa. Time zero was Day 56 (Month 2) for the 28-day treatment group and Month 3 for the 56-day treatment group. Kaplan-Meier estimates were used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Pseudomonas (P.) Aeruginosa Eradicated From Deep Throat Cough Swab or Sputum | From 1 month after the end of treatment until the end of the study (Month 27) | One month after the end of treatment was Day 56 (Month 2) for the 28-day treatment group and Month 3 for the 56-day treatment group. |
| Time to Recurrence of Pseudomonas (P.) Aeruginosa (New or Same Genotype) in Sputum or Deep Throat Cough Swab Based on Confirmatory Assessment by the Central Laboratory | From 1 month after the end of treatment until the end of the study (Month 27) | Time to recurrence was defined as the time between the visit at 1 month after the end of treatment (when eradication was confirmed) and the time of the first positive culture with any genotype of P. aeruginosa. Time zero was Day 56 (Month 2) for the 28-day treatment group and Month 3 for the 56-day treatment group. |
| Percentage of Patients With Pseudomonas (P.) Aeruginosa Having an Increased, Decreased, or Unchanged Tobramycin Minimum Inhibitory Concentration (MIC) Value at the Final Visit Compared to Baseline | From Baseline to the final visit (end of the study, Month 27) | The percentage of patients with changes in tobramycin MIC values from Baseline to the final visit could not be compared as there was insufficient data. |
| Number of Participants Hospitalized for Pulmonary Exacerbations | From Baseline to end of study (27 months) | Core study defined as from Baseline through to one month after the end of treatment (Day 56 for the 28-day treatment group and Month 3 for the 56-day treatment group). Follow-up phase began at the end of the core study through to the end of the study (Month 27). |
Participant flow
Pre-assignment details
123 patients were enrolled and received tobramycin 300 mg twice a day for 28 days. Patients who received treatment but tested positive for antibodies to any of 3 Pseudomonas aeruginosa exoenzymes in a blood sample collected at baseline were not randomized into one of the two treatment groups but were followed-up during routine clinic visits.
Participants by arm
| Arm | Count |
|---|---|
| Tobramycin 300 mg for 28 Days Patients inhaled tobramycin 300 mg twice a day for 28 days using the PARI LC PLUS™ jet nebulizer and a suitable compressor. The 2 daily doses were taken approximately 12 hours apart and no less than 6 hours apart. | 45 |
| Tobramycin 300 mg for 56 Days Patients inhaled tobramycin 300 mg twice a day for 56 days using the PARI LC PLUS™ jet nebulizer and a suitable compressor. The 2 daily doses were taken approximately 12 hours apart and no less than 6 hours apart. | 43 |
| Non-randomized Patients Patients who started the study and received tobramycin 300 mg twice a day for 28 days, but tested positive for antibodies to any of 3 Pseudomonas aeruginosa exoenzymes in a blood sample collected at baseline were not randomized into the treatment groups. These patients were not included in the efficacy analyses. | 35 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Inappropriate enrollment | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 0 |
| Overall Study | Positive P. aeruginosa antibody test | 0 | 0 | 31 |
| Overall Study | Protocol deviation/violation | 4 | 2 | 1 |
| Overall Study | Recurrence/no eradication of infection | 21 | 19 | 0 |
| Overall Study | Unable to classify | 0 | 0 | 1 |
| Overall Study | Withdrawal of consent | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Tobramycin 300 mg for 28 Days | Tobramycin 300 mg for 56 Days | Non-randomized Patients | Total |
|---|---|---|---|---|
| Age Continuous | 8.70 years STANDARD_DEVIATION 7.22 | 8.65 years STANDARD_DEVIATION 10.54 | 9.09 years STANDARD_DEVIATION 5.76 | 8.79 years STANDARD_DEVIATION 8.14 |
| Age, Customized ≥ 18 years | 6 participants | 4 participants | 3 participants | 13 participants |
| Age, Customized 6 months - < 6 years | 19 participants | 18 participants | 11 participants | 48 participants |
| Age, Customized 6 years - < 18 years | 20 participants | 21 participants | 21 participants | 62 participants |
| Sex: Female, Male Female | 19 Participants | 21 Participants | 19 Participants | 59 Participants |
| Sex: Female, Male Male | 26 Participants | 22 Participants | 16 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 44 | 14 / 43 | 3 / 35 | 19 / 35 | 18 / 36 |
| serious Total, serious adverse events | 4 / 44 | 3 / 43 | 1 / 35 | 2 / 35 | 2 / 36 |
Outcome results
Primary
Time to Recurrence of Pseudomonas (P.) Aeruginosa (Any Genotype) in Sputum or Deep Throat Cough Swab
Microbiological samples were obtained from sputum or by deep throat cough swab technique. Time to recurrence was defined as the time between the visit at 1 month after the end of treatment (when eradication was confirmed) and the time of the first positive culture with any genotype of P. aeruginosa. Time zero was Day 56 (Month 2) for the 28-day treatment group and Month 3 for the 56-day treatment group. Kaplan-Meier estimates were used.
Time frame: From 1 month after the end of treatment (Day 56 for the 28-day treatment group and Month 3 for the 56-day treatment group) until the end of the study (Month 27)
Population: Efficacy evaluable population: All randomized patients who had microbiological assessments 1 month after their last dose of study drug, except for patients with no eradication 1 month after the last dose of study drug, low compliance (\> 50% of capsules returned unused), or violation of protocol procedure in relation to the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tobramycin 300 mg for 28 Days | Time to Recurrence of Pseudomonas (P.) Aeruginosa (Any Genotype) in Sputum or Deep Throat Cough Swab | 26.12 Months |
| Tobramycin 300 mg for 56 Days | Time to Recurrence of Pseudomonas (P.) Aeruginosa (Any Genotype) in Sputum or Deep Throat Cough Swab | 25.82 Months |
Secondary
Number of Participants Hospitalized for Pulmonary Exacerbations
Core study defined as from Baseline through to one month after the end of treatment (Day 56 for the 28-day treatment group and Month 3 for the 56-day treatment group). Follow-up phase began at the end of the core study through to the end of the study (Month 27).
Time frame: From Baseline to end of study (27 months)
Population: All patients who were randomized and received at least one dose of study medication. Non-randomized patients were not included in the analysis.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Tobramycin 300 mg for 28 Days | Number of Participants Hospitalized for Pulmonary Exacerbations | Core Study | 0 Participants | — |
| Tobramycin 300 mg for 28 Days | Number of Participants Hospitalized for Pulmonary Exacerbations | Follow-up | 5 Participants | — |
| Tobramycin 300 mg for 56 Days | Number of Participants Hospitalized for Pulmonary Exacerbations | Core Study | 2 Participants | 9.2 |
| Tobramycin 300 mg for 56 Days | Number of Participants Hospitalized for Pulmonary Exacerbations | Follow-up | 2 Participants | — |
Secondary
Percentage of Patients With Pseudomonas (P.) Aeruginosa Eradicated From Deep Throat Cough Swab or Sputum
One month after the end of treatment was Day 56 (Month 2) for the 28-day treatment group and Month 3 for the 56-day treatment group.
Time frame: From 1 month after the end of treatment until the end of the study (Month 27)
Population: Efficacy evaluable population: All randomized patients who had microbiological assessments 1 month after their last dose of study drug, except for patients with no eradication 1 month after the last dose of study drug, low compliance (\> 50% of capsules returned unused), or violation of protocol procedure in relation to the efficacy analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tobramycin 300 mg for 28 Days | Percentage of Patients With Pseudomonas (P.) Aeruginosa Eradicated From Deep Throat Cough Swab or Sputum | At 1 month after the end of treatment | 100 Percentage of participants |
| Tobramycin 300 mg for 28 Days | Percentage of Patients With Pseudomonas (P.) Aeruginosa Eradicated From Deep Throat Cough Swab or Sputum | At final visit | 68 Percentage of participants |
| Tobramycin 300 mg for 56 Days | Percentage of Patients With Pseudomonas (P.) Aeruginosa Eradicated From Deep Throat Cough Swab or Sputum | At 1 month after the end of treatment | 100 Percentage of participants |
| Tobramycin 300 mg for 56 Days | Percentage of Patients With Pseudomonas (P.) Aeruginosa Eradicated From Deep Throat Cough Swab or Sputum | At final visit | 71 Percentage of participants |
Secondary
Percentage of Patients With Pseudomonas (P.) Aeruginosa Having an Increased, Decreased, or Unchanged Tobramycin Minimum Inhibitory Concentration (MIC) Value at the Final Visit Compared to Baseline
The percentage of patients with changes in tobramycin MIC values from Baseline to the final visit could not be compared as there was insufficient data.
Time frame: From Baseline to the final visit (end of the study, Month 27)
Population: Safety population: All patients who were enrolled in the study and received at least 1 dose of study medication.
Secondary
Time to Recurrence of Pseudomonas (P.) Aeruginosa (New or Same Genotype) in Sputum or Deep Throat Cough Swab Based on Confirmatory Assessment by the Central Laboratory
Time to recurrence was defined as the time between the visit at 1 month after the end of treatment (when eradication was confirmed) and the time of the first positive culture with any genotype of P. aeruginosa. Time zero was Day 56 (Month 2) for the 28-day treatment group and Month 3 for the 56-day treatment group.
Time frame: From 1 month after the end of treatment until the end of the study (Month 27)
Population: Efficacy evaluable population: All randomized patients who had microbiological assessments 1 month after their last dose of study drug, except for patients with no eradication 1 month after the last dose of study drug, low compliance (\> 50% of capsules returned unused), or violation of protocol procedure in relation to the efficacy analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Tobramycin 300 mg for 28 Days | Time to Recurrence of Pseudomonas (P.) Aeruginosa (New or Same Genotype) in Sputum or Deep Throat Cough Swab Based on Confirmatory Assessment by the Central Laboratory | 9.84 Months | 95% Confidence Interval 2.47 |
| Tobramycin 300 mg for 56 Days | Time to Recurrence of Pseudomonas (P.) Aeruginosa (New or Same Genotype) in Sputum or Deep Throat Cough Swab Based on Confirmatory Assessment by the Central Laboratory | 16.62 Months | 95% Confidence Interval 2.61 |