Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, Respiratory Infections, Pulmonary Cystic Fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR), Anti-bacterial Agent, Arikayce, ALIS, LAI
Brief summary
The purpose of this study is to evaluate the long term safety and tolerability of Liposomal Amikacin for Inhalation (LAI) 590 mg once daily (QD) in Cystic Fibrosis patients with chronic infection due to pseudomonas aeruginosa. This long-term, open-label, multi-cycle extension study enrolled subjects who had successfully completed study TR02-108, were compliant with the study protocol, and did not meet any of the listed study discontinuation criteria. The safety and tolerability of LAI were evaluated for up to approximately 2 years.
Detailed description
This was a long-term, open-label, multi-cycle extension study for patients in the Phase 3 study TR02-108 and TR02-109 who had successfully completed the 168-day study period and met study safety criteria. As this was a safety and tolerability long-term extension study, no sample size calculations were performed. All patients who completed TR02-108, were compliant with the study protocol, and did not meet any of the criteria listed for study discontinuation (safety reasons or non-compliance) were able to participate in this open-label study. The end of study visit for TR02-108 was to serve as the baseline study visit (Day 1) for TR02-110 if the patient had signed the informed consent at least 4 days prior to the end of study visit and met all safety criteria for TR02-110. If the end of study visit was not used as the baseline visit, a separate baseline visit (Day 1) was to be performed within 14 days of completing TR02-108. Patients were to receive a delivered dose of 590 mg LAI QD via a PARI Investigational eFlow® Nebulizer System (eFlow®) for 28 days followed by a 28-day off-treatment period. This cycle (28 days on treatment, 28 days off treatment) was to be repeated for up to 12 cycles. The study was implemented as 2 consecutive extension periods, each consisting of 48 weeks (approximately 12 months). Patients were re-consented for the second extension period at the completion of the first extension period. The total study period was up to 96 weeks (approximately 2 years). During the first 28 days of treatment, patients were evaluated at the study site bi-weekly for safety, tolerability and efficacy. Thereafter, for the duration of the study, patients were evaluated at the study site on the first and last days of dosing during the on-treatment periods. During the study, starting with the off-treatment period of Cycle 1, patients were contacted by telephone once during every 28-day period to assess safety. A final site visit occurred 28 days after last dose of LAI. Arikace™, Arikayce™,Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and other studies evaluating amikacin liposome inhalation suspension.
Interventions
* Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. * 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. * Administration time is approximately 13 minutes. * Liposomal amikacin for inhalation will be administered in two consecutive extension periods, each consisting of 6 cycles for a total of 12 cycles. Each cycle consists of 28 days on-treatment followed by 28 days off-treatment.
Sponsors
Insmed Incorporated
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Written informed consent or assent * Subject has completed study TR02-108, and has been compliant with the study protocol * Women of childbearing potential must agree to use reliable methods of contraception for the duration of the study Key
Exclusion criteria
* Subject met any of the listed criteria for study drug discontinuation in protocol TR02-108. * Abnormal laboratory assessments including LFT (≥ 3× upper limit of normal \[ULN\]), serum creatinine (\> 2× ULN) and absolute neutrophil count \[ANC\] (\< 1000). * Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements. * History of alcohol, medication or illicit drug abuse within the 6 months prior to consent. * Smoking tobacco or any substance within 6 months prior to consent or anticipated inability to refrain from smoking throughout the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Creatinine Throughout the Study | Baseline, Day 337 and Day 672 | * Common Terminology Criteria for Adverse Events (CTCAE) Grade 1: \> ULN-1.5 × ULN * CTCAE Grade 2: \> 1.5 × ULN to 3.0 x ULN |
| Body Temperature: Change From Baseline at Day 672 | From Study Initiation up to Day 672 | Body temperature was recorded at every visit as per standard practice at each investigational site. |
| Oxygen Saturation: Change From Baseline at Day 672 | From Study Initiation up to Day 672 | Change in oxygen saturation as measured with pulse oximetry was performed via finger probes placed on the extremity opposite arterial lines and noninvasive blood pressure monitoring devices so that pulsatile flow was not interrupted. |
| Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Day 1, Day 169, Day 337, Day 505 and Day 672 | Sputum was cultured for quantitative microbiological evaluation of Pa and Burkholderia species in designated regional central microbiology laboratories. A standard microbiology protocol was used for Pa culture and identification for each morphologically distinct Pa phenotype. Although planned in the Statistical Analysis Plan (SAP), MICs of amikacin Burkholderia species were not determined due to the small number of isolates with Burkholderia. In addition, susceptibility testing of isolates of Pa and Burkholderia species against a panel of commonly used antipseudomonal antibiotics was planned but was not performed. The results of the following analyses for Pa isolates are presented. * Frequency of MIC of Amikacin * Frequency of MIC of Tobramycin MIC50: lowest concentration of the antibiotic at which 50 % of the isolates were inhibited. |
| Evaluation of Audiology | Day 337 and Day 672 | Hearing was evaluated using air conduction \[AC\]. Bone conduction was required if the AC testing demonstrated a decrease of \>20 decibels \[dB\]. Hearing loss was categorized using Common Terminology Criteria for Adverse Events as follows: GRADE 1 (best): Adults \[A\] on a Monitoring Program \[MP\]: Threshold shift of 15-25 dB; Pediatric \[P\]: Threshold shift \>20 dB at 8 kilohertz (kHz). GRADE 2: \[A\] on a MP: Threshold shift of \>25 dB; \[A\] not enrolled in MP: hearing loss; hearing aid/intervention not indicated; \[P\]: Threshold shift \>20 dB at 4 kHz and above. GRADE 3: \[A\] enrolled in MP: Threshold shift of \>25 dB; therapeutic intervention indicated; \[A\]: Not enrolled in MP: hearing aid/intervention; \[P\]: therapeutic intervention, including hearing aids: Threshold shift \>20 dB at 3 kHz and above; additional speech-language related services. GRADE 4 (worst): \[A\]: Profound bilateral hearing loss; non-serviceable hearing; \[P\]: cochlear implant & additional speech-language related services. |
| Treatment Emergent Adverse Events (TEAEs) up to Day 672 | From Study Initiation up to Day 672 | Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug |
| Laboratory Abnormalities up to Day 672 | Baseline, Day 377 and Day 672 | * Number of Subjects with Grade 3 or Higher Abnormalities in Clinical Laboratory Values * Number of Subjects with Grade 3 or Higher Hematology Laboratory Value Abnormalities * Number of Subjects with Grade 3 or Higher Chemistry Laboratory Value Abnormalities |
| Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 1, Day 84, Day 196, Day 281, Day 337, Day 449, Day 532 and Day 644 | Number of Subjects with a \>15% in Decline in Forced Expiratory Volume in 1 Second (FEV1) From Predose to Postdose |
| Respiratory Rate: Change From Baseline to Day 672 | From Study Initiation up to Day 672 | Respiratory rate was recorded at every visit as per standard practice at each investigational site. |
| Heart Rate: Change From Baseline From Day 672 | From Study Initiation up to Day 672 | Pulse rate (after at least 5-minute rest) was recorded at every visit as per standard practice at each investigational site. |
| Systolic BP: Change From Baseline at Day 672 | From Study Initiation up to Day 672 | Sitting blood pressure was recorded at every visit as per standard practice at each investigational site. |
| Diastolic BP: Change From Baseline at Day 672 | From Study Initiation up to Day 672 | Sitting blood pressure was recorded at every visit as per standard practice at each investigational site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation | From Study Initiation up to Day 700 | For number of subjects to first protocol-defined pulmonary exacerbation, follow-up time began at the first dose of study drug (Day 1) and ended no later than Day 700 (28-day follow up). |
| Number of Subjects Initiating Treatment. | From Study Initiation up to Day 672 | The number of subjects initiating antipseudomonal therapy for protocol-defined pulmonary exacerbation confirmed by the investigator, and for investigator-defined pulmonary exacerbation were summarized. The data presented below is the Frequency of Systemic or Inhaled Antipseudomonal Therapy for Protocol-defined Pulmonary Exacerbations Confirmed by Investigator \- Time to First Use of Any New Antibiotic Treatment, Censoring at Date of Last Contact |
| Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation | From Study Initiation up to Day 700 | — |
| Percent Change in FEV1 Throughout the Study | Baseline, Day 337 and Day 672 | Percent Change From Baseline in Predose FEV1 |
Countries
Austria, Belgium, Bulgaria, Canada, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Serbia, Slovakia, Spain, United Kingdom
Participant flow
Recruitment details
Study TR02-110 did not include any patients from Study TR02-109 since that study never enrolled patients.
Participants by arm
| Arm | Count |
|---|---|
| LAI 590 mg QD 590 mg LAI QD via a PARI Investigational eFlow® Nebulizer System (eFlow®) for 28 days followed by a 28-day off-treatment period. This cycle (28 days on treatment, 28 days off treatment) was to be repeated for up to 12 cycles, divided into 2 periods of 6 cycles each (approximately 12 months each).
Liposomal amikacin for inhalation: - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization.
* 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer.
* Administration time is approximately 13 minutes.
* Liposomal amikacin for inhalation will be administered in two consecutive extension periods, each consisting of 6 cycles for a total of 12 cycles. Each cycle consists of 28 days on-treatment followed by 28 days off-treatment. | 206 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 19 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 22 |
| Overall Study | Withdrawal of consent | 24 |
Baseline characteristics
| Characteristic | LAI 590 mg QD |
|---|---|
| Age, Continuous Baseline age (years) | 21.0 years STANDARD_DEVIATION 9.73 |
| Age, Customized Age Age group at baseline: >12 to 18 years | 62 Participants |
| Age, Customized Age Age group at baseline: >18 years | 107 Participants |
| Age, Customized Age Age group at baseline: 6 to 12 years | 37 Participants |
| Geographic region Central Europe / Eastern Europe | 107 Participants |
| Geographic region Western Europe / North America | 99 Participants |
| Race/Ethnicity, Customized Ethnicity African | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Caucasian (not of Hispanic origin) | 200 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic | 5 Participants |
| Sex: Female, Male Female | 103 Participants |
| Sex: Female, Male Male | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 206 |
| other Total, other adverse events | 167 / 206 |
| serious Total, serious adverse events | 92 / 206 |
Outcome results
Primary
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Number of Subjects with a \>15% in Decline in Forced Expiratory Volume in 1 Second (FEV1) From Predose to Postdose
Time frame: Day 1, Day 84, Day 196, Day 281, Day 337, Day 449, Day 532 and Day 644
Population: Safety Population~Patients with missing values were excluded.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 1 | 6 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 84 | 6 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 196 | 1 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 281 | 5 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 337 | 5 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 449 | 6 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 532 | 2 Participants |
| LAI 590 mg QD | Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose | Day 644 | 3 Participants |
Primary
Body Temperature: Change From Baseline at Day 672
Body temperature was recorded at every visit as per standard practice at each investigational site.
Time frame: From Study Initiation up to Day 672
Population: Safety Population Patients with missing data were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAI 590 mg QD | Body Temperature: Change From Baseline at Day 672 | 0.03 Degrees Celcius | Standard Deviation 0.316 |
Primary
Change in Serum Creatinine Throughout the Study
* Common Terminology Criteria for Adverse Events (CTCAE) Grade 1: \> ULN-1.5 × ULN * CTCAE Grade 2: \> 1.5 × ULN to 3.0 x ULN
Time frame: Baseline, Day 337 and Day 672
Population: Safety Population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 1: Baseline | yes | 1 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 1: Baseline | no | 205 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 1: Day 337/End of Study Year 1 | yes | 0 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 1: Day 337/End of Study Year 1 | no | 158 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 1: Day 672/End of Study Year 2 | yes | 0 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 1: Day 672/End of Study Year 2 | no | 131 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 2: Baseline | yes | 0 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 2: Baseline | no | 206 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 2: Day 337/End of Study Year 1 | yes | 0 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 2: Day 337/End of Study Year 1 | no | 158 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 2: Day 672/End of Study Year 2 | yes | 0 Participants |
| LAI 590 mg QD | Change in Serum Creatinine Throughout the Study | CTCAE Grade 2: Day 672/End of Study Year 2 | no | 131 Participants |
Primary
Diastolic BP: Change From Baseline at Day 672
Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
Time frame: From Study Initiation up to Day 672
Population: Safety Population Patients with missing data were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAI 590 mg QD | Diastolic BP: Change From Baseline at Day 672 | 1.5 mmHg | Standard Deviation 9.16 |
Primary
Evaluation of Audiology
Hearing was evaluated using air conduction \[AC\]. Bone conduction was required if the AC testing demonstrated a decrease of \>20 decibels \[dB\]. Hearing loss was categorized using Common Terminology Criteria for Adverse Events as follows: GRADE 1 (best): Adults \[A\] on a Monitoring Program \[MP\]: Threshold shift of 15-25 dB; Pediatric \[P\]: Threshold shift \>20 dB at 8 kilohertz (kHz). GRADE 2: \[A\] on a MP: Threshold shift of \>25 dB; \[A\] not enrolled in MP: hearing loss; hearing aid/intervention not indicated; \[P\]: Threshold shift \>20 dB at 4 kHz and above. GRADE 3: \[A\] enrolled in MP: Threshold shift of \>25 dB; therapeutic intervention indicated; \[A\]: Not enrolled in MP: hearing aid/intervention; \[P\]: therapeutic intervention, including hearing aids: Threshold shift \>20 dB at 3 kHz and above; additional speech-language related services. GRADE 4 (worst): \[A\]: Profound bilateral hearing loss; non-serviceable hearing; \[P\]: cochlear implant & additional speech-language related services.
Time frame: Day 337 and Day 672
Population: Safety Population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | Grade 3 | 0 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | None or minimal change | 133 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | Grade 1 | 2 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | Grade 2 | 0 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | Grade 4 | 0 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | Indeterminate | 26 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 337/End of Study Day 337 | Missing | 45 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | None or minimal change | 120 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | Grade 1 | 6 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | Grade 2 | 0 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | Grade 3 | 1 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | Grade 4 | 0 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | Indeterminate | 7 Participants |
| LAI 590 mg QD | Evaluation of Audiology | Day 672/End of Study Day 672 | Missing | 72 Participants |
Primary
Heart Rate: Change From Baseline From Day 672
Pulse rate (after at least 5-minute rest) was recorded at every visit as per standard practice at each investigational site.
Time frame: From Study Initiation up to Day 672
Population: Safety Population Patients with missing data were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAI 590 mg QD | Heart Rate: Change From Baseline From Day 672 | -0.9 beats/min | Standard Deviation 12.46 |
Primary
Laboratory Abnormalities up to Day 672
* Number of Subjects with Grade 3 or Higher Abnormalities in Clinical Laboratory Values * Number of Subjects with Grade 3 or Higher Hematology Laboratory Value Abnormalities * Number of Subjects with Grade 3 or Higher Chemistry Laboratory Value Abnormalities
Time frame: Baseline, Day 377 and Day 672
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Lymphocytes (<0.5 × 109 /L) | 12 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Neutrophils (<2.0 × 109 /L) | 23 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Platelets (<192 × 109 /L) | 1 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Alanine aminotransferase (>5.0 × ULN) | 2 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Aspartate aminotransferase (>5.0 × ULN) | 1 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Baseline | 13 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Day 337/End of Study Year 1 | 8 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Day 672/End of Study Year 2 | 8 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Leukocytes (<2.0 × 109 /L) | 7 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Gamma-glutamyltransferase (>5.0 × ULN) | 2 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Indirect bilirubin (>3.0 × ULN) | 1 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Calcium (<2.1 mmol/L) | 1 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Serum glucose: >13.9 mmol/L | 14 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Serum glucose: < 2.2 mmol/L | 6 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Phosphate (<0.6 mmol/L) | 3 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Potassium: >6.0 mmol/L | 8 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Potassium: <3.6 mmol/L | 1 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Sodium: >155 mmol/L | 1 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Sodium: <130 mmol/L | 4 Participants |
| LAI 590 mg QD | Laboratory Abnormalities up to Day 672 | Urate (> ULN with physiologic consequences) | 8 Participants |
Primary
Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672
Sputum was cultured for quantitative microbiological evaluation of Pa and Burkholderia species in designated regional central microbiology laboratories. A standard microbiology protocol was used for Pa culture and identification for each morphologically distinct Pa phenotype. Although planned in the Statistical Analysis Plan (SAP), MICs of amikacin Burkholderia species were not determined due to the small number of isolates with Burkholderia. In addition, susceptibility testing of isolates of Pa and Burkholderia species against a panel of commonly used antipseudomonal antibiotics was planned but was not performed. The results of the following analyses for Pa isolates are presented. * Frequency of MIC of Amikacin * Frequency of MIC of Tobramycin MIC50: lowest concentration of the antibiotic at which 50 % of the isolates were inhibited.
Time frame: Day 1, Day 169, Day 337, Day 505 and Day 672
Population: Safety Population~Patients with missing data were excluded.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Amikacin MIC50: Day 337 | 16.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Amikacin MIC50: Day 1 | 16.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Amikacin MIC50: Day 169 | 16.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Amikacin MIC50: Day 505 | 16.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Amikacin MIC50: Day 672 | 16.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Tobramycin MIC50: Day 1 | 2.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Tobramycin MIC50: Day 169 | 2.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Tobramycin MIC50: Day 337 | 2.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Tobramycin MIC50: Day 505 | 2.000 µg/mL |
| LAI 590 mg QD | Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672 | Tobramycin MIC50: Day 672 | 1.000 µg/mL |
Primary
Oxygen Saturation: Change From Baseline at Day 672
Change in oxygen saturation as measured with pulse oximetry was performed via finger probes placed on the extremity opposite arterial lines and noninvasive blood pressure monitoring devices so that pulsatile flow was not interrupted.
Time frame: From Study Initiation up to Day 672
Population: Safety Population Patients with missing data were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAI 590 mg QD | Oxygen Saturation: Change From Baseline at Day 672 | -0.1 Percent of Hemoglobin | Standard Deviation 1.47 |
Primary
Respiratory Rate: Change From Baseline to Day 672
Respiratory rate was recorded at every visit as per standard practice at each investigational site.
Time frame: From Study Initiation up to Day 672
Population: Safety Population Patients with missing data were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAI 590 mg QD | Respiratory Rate: Change From Baseline to Day 672 | -0.8 breaths per minute | Standard Deviation 3.02 |
Primary
Systolic BP: Change From Baseline at Day 672
Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
Time frame: From Study Initiation up to Day 672
Population: Safety Population Patients with missing data were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAI 590 mg QD | Systolic BP: Change From Baseline at Day 672 | 2.3 mmHg | Standard Deviation 11.39 |
Primary
Treatment Emergent Adverse Events (TEAEs) up to Day 672
Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug
Time frame: From Study Initiation up to Day 672
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAI 590 mg QD | Treatment Emergent Adverse Events (TEAEs) up to Day 672 | Patients with ≥1 treatment-emergent AE | 183 Participants |
| LAI 590 mg QD | Treatment Emergent Adverse Events (TEAEs) up to Day 672 | Patients with ≥ 1 serious AE | 92 Participants |
| LAI 590 mg QD | Treatment Emergent Adverse Events (TEAEs) up to Day 672 | Patients with ≥1 AE leading to discontinuation | 21 Participants |
Secondary
Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation
Time frame: From Study Initiation up to Day 700
Population: mITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAI 590 mg QD | Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation | Number of patients with the event through Day 700 | 148 Participants |
| LAI 590 mg QD | Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation | Number censored | 58 Participants |
Secondary
Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation
For number of subjects to first protocol-defined pulmonary exacerbation, follow-up time began at the first dose of study drug (Day 1) and ended no later than Day 700 (28-day follow up).
Time frame: From Study Initiation up to Day 700
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LAI 590 mg QD | Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation | Number of patients with the event through Day 700 | 151 participants |
| LAI 590 mg QD | Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation | Number censored | 55 participants |
Secondary
Number of Subjects Initiating Treatment.
The number of subjects initiating antipseudomonal therapy for protocol-defined pulmonary exacerbation confirmed by the investigator, and for investigator-defined pulmonary exacerbation were summarized. The data presented below is the Frequency of Systemic or Inhaled Antipseudomonal Therapy for Protocol-defined Pulmonary Exacerbations Confirmed by Investigator \- Time to First Use of Any New Antibiotic Treatment, Censoring at Date of Last Contact
Time frame: From Study Initiation up to Day 672
Population: mITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAI 590 mg QD | Number of Subjects Initiating Treatment. | After Day 1 through Day 337 | 81 Participants |
| LAI 590 mg QD | Number of Subjects Initiating Treatment. | After Day 1 through Day 672 | 108 Participants |
Secondary
Percent Change in FEV1 Throughout the Study
Percent Change From Baseline in Predose FEV1
Time frame: Baseline, Day 337 and Day 672
Population: modified intention to treat (mITT) population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LAI 590 mg QD | Percent Change in FEV1 Throughout the Study | Baseline | 2.104 Percent (%) change | Standard Deviation 0.865 |
| LAI 590 mg QD | Percent Change in FEV1 Throughout the Study | Day 337 | 2.36 Percent (%) change | Standard Deviation 14.359 |
| LAI 590 mg QD | Percent Change in FEV1 Throughout the Study | Day 672 | 3.62 Percent (%) change | Standard Deviation 18.485 |