Trial Outcomes & Findings for Extension Study of Liposomal Amikacin for Inhalation in Cystic Fibrosis (CF) Patients With Chronic Pseudomonas Aeruginosa (Pa) Infection (NCT NCT01316276)
NCT ID: NCT01316276
Last Updated: 2020-06-17
Results Overview
Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
206 participants
Primary outcome timeframe
From Study Initiation up to Day 672
Results posted on
2020-06-17
Participant Flow
Study TR02-110 did not include any patients from Study TR02-109 since that study never enrolled patients.
Participant milestones
| Measure |
LAI 590 mg QD
590 mg LAI once a day (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 (LAI): - 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.
|
|---|---|
|
Overall Study
STARTED
|
206
|
|
Overall Study
COMPLETED
|
139
|
|
Overall Study
NOT COMPLETED
|
67
|
Reasons for withdrawal
| Measure |
LAI 590 mg QD
590 mg LAI once a day (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 (LAI): - 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.
|
|---|---|
|
Overall Study
Death
|
1
|
|
Overall Study
Adverse Event
|
19
|
|
Overall Study
Withdrawal of consent
|
24
|
|
Overall Study
Lost to Follow-up
|
1
|
|
Overall Study
Other
|
22
|
Baseline Characteristics
Extension Study of Liposomal Amikacin for Inhalation in Cystic Fibrosis (CF) Patients With Chronic Pseudomonas Aeruginosa (Pa) Infection
Baseline characteristics by cohort
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Age, Continuous
Baseline age (years)
|
21.0 years
STANDARD_DEVIATION 9.73 • n=5 Participants
|
|
Age, Customized
Age · Age group at baseline: 6 to 12 years
|
37 Participants
n=5 Participants
|
|
Age, Customized
Age · Age group at baseline: >12 to 18 years
|
62 Participants
n=5 Participants
|
|
Age, Customized
Age · Age group at baseline: >18 years
|
107 Participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
103 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
103 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Ethnicity · Caucasian (not of Hispanic origin)
|
200 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Ethnicity · Hispanic
|
5 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Ethnicity · African
|
1 Participants
n=5 Participants
|
|
Geographic region
Western Europe / North America
|
99 Participants
n=5 Participants
|
|
Geographic region
Central Europe / Eastern Europe
|
107 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population
Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Treatment Emergent Adverse Events (TEAEs) up to Day 672
Patients with ≥1 treatment-emergent AE
|
183 Participants
|
|
Treatment Emergent Adverse Events (TEAEs) up to Day 672
Patients with ≥ 1 serious AE
|
92 Participants
|
|
Treatment Emergent Adverse Events (TEAEs) up to Day 672
Patients with ≥1 AE leading to discontinuation
|
21 Participants
|
PRIMARY outcome
Timeframe: Baseline, Day 377 and Day 672Population: Safety Population
* 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
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Laboratory Abnormalities up to Day 672
Phosphate (<0.6 mmol/L)
|
3 Participants
|
|
Laboratory Abnormalities up to Day 672
Baseline
|
13 Participants
|
|
Laboratory Abnormalities up to Day 672
Day 337/End of Study Year 1
|
8 Participants
|
|
Laboratory Abnormalities up to Day 672
Day 672/End of Study Year 2
|
8 Participants
|
|
Laboratory Abnormalities up to Day 672
Leukocytes (<2.0 × 109 /L)
|
7 Participants
|
|
Laboratory Abnormalities up to Day 672
Lymphocytes (<0.5 × 109 /L)
|
12 Participants
|
|
Laboratory Abnormalities up to Day 672
Neutrophils (<2.0 × 109 /L)
|
23 Participants
|
|
Laboratory Abnormalities up to Day 672
Platelets (<192 × 109 /L)
|
1 Participants
|
|
Laboratory Abnormalities up to Day 672
Alanine aminotransferase (>5.0 × ULN)
|
2 Participants
|
|
Laboratory Abnormalities up to Day 672
Aspartate aminotransferase (>5.0 × ULN)
|
1 Participants
|
|
Laboratory Abnormalities up to Day 672
Gamma-glutamyltransferase (>5.0 × ULN)
|
2 Participants
|
|
Laboratory Abnormalities up to Day 672
Indirect bilirubin (>3.0 × ULN)
|
1 Participants
|
|
Laboratory Abnormalities up to Day 672
Calcium (<2.1 mmol/L)
|
1 Participants
|
|
Laboratory Abnormalities up to Day 672
Serum glucose: >13.9 mmol/L
|
14 Participants
|
|
Laboratory Abnormalities up to Day 672
Serum glucose: < 2.2 mmol/L
|
6 Participants
|
|
Laboratory Abnormalities up to Day 672
Potassium: >6.0 mmol/L
|
8 Participants
|
|
Laboratory Abnormalities up to Day 672
Potassium: <3.6 mmol/L
|
1 Participants
|
|
Laboratory Abnormalities up to Day 672
Sodium: >155 mmol/L
|
1 Participants
|
|
Laboratory Abnormalities up to Day 672
Sodium: <130 mmol/L
|
4 Participants
|
|
Laboratory Abnormalities up to Day 672
Urate (> ULN with physiologic consequences)
|
8 Participants
|
PRIMARY outcome
Timeframe: Day 1, Day 84, Day 196, Day 281, Day 337, Day 449, Day 532 and Day 644Population: Safety Population Patients with missing values were excluded.
Number of Subjects with a \>15% in Decline in Forced Expiratory Volume in 1 Second (FEV1) From Predose to Postdose
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 1
|
6 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 449
|
6 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 532
|
2 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 84
|
6 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 196
|
1 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 281
|
5 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 337
|
5 Participants
|
|
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
Day 644
|
3 Participants
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population Patients with missing data were excluded.
Respiratory rate was recorded at every visit as per standard practice at each investigational site.
Outcome measures
| Measure |
LAI 590 mg QD
n=133 Participants
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.
|
|---|---|
|
Respiratory Rate: Change From Baseline to Day 672
|
-0.8 breaths per minute
Standard Deviation 3.02
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population Patients with missing data were excluded.
Pulse rate (after at least 5-minute rest) was recorded at every visit as per standard practice at each investigational site.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Heart Rate: Change From Baseline From Day 672
|
-0.9 beats/min
Standard Deviation 12.46
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population Patients with missing data were excluded.
Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Systolic BP: Change From Baseline at Day 672
|
2.3 mmHg
Standard Deviation 11.39
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population Patients with missing data were excluded.
Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Diastolic BP: Change From Baseline at Day 672
|
1.5 mmHg
Standard Deviation 9.16
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population Patients with missing data were excluded.
Body temperature was recorded at every visit as per standard practice at each investigational site.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Body Temperature: Change From Baseline at Day 672
|
0.03 Degrees Celcius
Standard Deviation 0.316
|
PRIMARY outcome
Timeframe: From Study Initiation up to Day 672Population: Safety Population Patients with missing data were excluded.
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.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Oxygen Saturation: Change From Baseline at Day 672
|
-0.1 Percent of Hemoglobin
Standard Deviation 1.47
|
PRIMARY outcome
Timeframe: Day 1, Day 169, Day 337, Day 505 and Day 672Population: Safety Population Patients with missing data were excluded.
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.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
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
Interval 1.0 to 2048.0
|
|
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
Interval 2.0 to 2048.0
|
|
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
Interval 1.0 to 2048.0
|
|
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
Interval 2.0 to 2048.0
|
|
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
Interval 0.25 to 2048.0
|
|
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
Interval 0.25 to 1024.0
|
|
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
Interval 0.12 to 1024.0
|
|
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
Interval 0.25 to 1024.0
|
|
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
Interval 0.12 to 1024.0
|
|
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
Interval 0.12 to 1024.0
|
PRIMARY outcome
Timeframe: Day 337 and Day 672Population: Safety Population
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.
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · None or minimal change
|
133 Participants
|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · Grade 1
|
2 Participants
|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · Grade 2
|
0 Participants
|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · Grade 3
|
0 Participants
|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · Grade 4
|
0 Participants
|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · Indeterminate
|
26 Participants
|
|
Evaluation of Audiology
Day 337/End of Study Day 337 · Missing
|
45 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · None or minimal change
|
120 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · Grade 1
|
6 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · Grade 2
|
0 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · Grade 3
|
1 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · Grade 4
|
0 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · Indeterminate
|
7 Participants
|
|
Evaluation of Audiology
Day 672/End of Study Day 672 · Missing
|
72 Participants
|
PRIMARY outcome
Timeframe: Baseline, Day 337 and Day 672Population: Safety Population
* Common Terminology Criteria for Adverse Events (CTCAE) Grade 1: \> ULN-1.5 × ULN * CTCAE Grade 2: \> 1.5 × ULN to 3.0 x ULN
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 1: Baseline · yes
|
1 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 1: Baseline · no
|
205 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 1: Day 337/End of Study Year 1 · yes
|
0 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 1: Day 337/End of Study Year 1 · no
|
158 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 1: Day 672/End of Study Year 2 · yes
|
0 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 1: Day 672/End of Study Year 2 · no
|
131 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 2: Baseline · yes
|
0 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 2: Baseline · no
|
206 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 2: Day 337/End of Study Year 1 · yes
|
0 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 2: Day 337/End of Study Year 1 · no
|
158 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 2: Day 672/End of Study Year 2 · yes
|
0 Participants
|
|
Change in Serum Creatinine Throughout the Study
CTCAE Grade 2: Day 672/End of Study Year 2 · no
|
131 Participants
|
SECONDARY outcome
Timeframe: Baseline, Day 337 and Day 672Population: modified intention to treat (mITT) population
Percent Change From Baseline in Predose FEV1
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Percent Change in FEV1 Throughout the Study
Baseline
|
2.104 Percent (%) change
Standard Deviation 0.8650
|
|
Percent Change in FEV1 Throughout the Study
Day 337
|
2.36 Percent (%) change
Standard Deviation 14.359
|
|
Percent Change in FEV1 Throughout the Study
Day 672
|
3.62 Percent (%) change
Standard Deviation 18.485
|
SECONDARY outcome
Timeframe: From Study Initiation up to Day 700Population: mITT
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).
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation
Number of patients with the event through Day 700
|
151 participants
|
|
Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation
Number censored
|
55 participants
|
SECONDARY outcome
Timeframe: From Study Initiation up to Day 672Population: mITT
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
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Number of Subjects Initiating Treatment.
After Day 1 through Day 337
|
81 Participants
|
|
Number of Subjects Initiating Treatment.
After Day 1 through Day 672
|
108 Participants
|
SECONDARY outcome
Timeframe: From Study Initiation up to Day 700Population: mITT Population
Outcome measures
| Measure |
LAI 590 mg QD
n=206 Participants
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.
|
|---|---|
|
Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation
Number of patients with the event through Day 700
|
148 Participants
|
|
Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation
Number censored
|
58 Participants
|
Adverse Events
LAI 590 mg QD
Serious events: 92 serious events
Other events: 167 other events
Deaths: 1 deaths
Serious adverse events
| Measure |
LAI 590 mg QD
n=206 participants at risk
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.
|
|---|---|
|
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
|
39.3%
81/206 • Number of events 139 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Appendicitis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Bronchitis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Bronchopulmonary aspergillosis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Gastroenteritis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Lung infection pseudomonal
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Measles
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Pneumonia
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Pyelonephritis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Respiratory tract infection
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Respiratory tract infection viral
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Urosepsis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Haemoptysis
|
1.5%
3/206 • Number of events 4 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
1.5%
3/206 • Number of events 4 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Atelectasis
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Nasal polyps
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Gastrointestinal disorders
Distal intestinal obstruction syndrome
|
0.97%
2/206 • Number of events 2 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Gastrointestinal disorders
Gastrointestinal obstruction
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Gastrointestinal disorders
Ileus
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Gastrointestinal disorders
Intestinal obstruction
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Gastrointestinal disorders
Rectal haemorrhage
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Nervous system disorders
Cerebrospinal fluid rhinorrhoea
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Nervous system disorders
Epilepsy
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Nervous system disorders
Neurological symptom
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
General disorders
Chest pain
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
General disorders
Non-cardiac chest pain
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Cardiac disorders
Cardiac failure
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Investigations
Pulmonary function test decreased
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Metabolism and nutrition disorders
Malnutrition
|
0.49%
1/206 • Number of events 1 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
Other adverse events
| Measure |
LAI 590 mg QD
n=206 participants at risk
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.
|
|---|---|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
7.8%
16/206 • Number of events 26 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Gastrointestinal disorders
Diarrhoea
|
7.3%
15/206 • Number of events 23 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
General disorders
Pyrexia
|
6.3%
13/206 • Number of events 15 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
|
62.6%
129/206 • Number of events 359 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Nasopharyngitis
|
25.2%
52/206 • Number of events 88 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Upper respiratory tract infection
|
15.5%
32/206 • Number of events 64 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Pharyngitis
|
8.7%
18/206 • Number of events 20 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Rhinitis
|
7.8%
16/206 • Number of events 19 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Sinusitis
|
7.3%
15/206 • Number of events 18 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Viral infection
|
7.3%
15/206 • Number of events 15 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Infections and infestations
Bronchitis
|
5.3%
11/206 • Number of events 15 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Nervous system disorders
Headache
|
9.2%
19/206 • Number of events 25 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Haemoptysis
|
14.6%
30/206 • Number of events 69 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
13.1%
27/206 • Number of events 45 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
|
Respiratory, thoracic and mediastinal disorders
Dysphonia
|
12.1%
25/206 • Number of events 40 • From enrollment up to a maximum of 672 Days (end of study, year 2)
|
Additional Information
Kevin Mange (Senior VP, Clinical Development)
Insmed Incorporated
Phone: 908-947-2651
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee Per the signed Investigator Agreement in the protocol and protocol amendments, the PI agreed that the information presented in the study protocol is confidential, and assured that no information based on the conduct of the study was released without prior Insmed Incorporated Consent, unless the requirement is superseded by the Food and Drug Administration or other regulatory authority.
- Publication restrictions are in place
Restriction type: OTHER