NTM Lung Infection Due to MAC
Conditions
Keywords
ALIS, ARIKAYCE
Brief summary
This is an open-label safety extension study to assess the safety and tolerability of once daily dosing of 590 mg Liposomal Amikacin for Inhalation (LAI) added to a multi-drug regimen in participants with nontuberculous mycobacterial (NTM) lung infections due to Mycobacterium avium complex (MAC) who were refractory to therapy and failed to convert in Study INS-212 (NCT02344004).
Detailed description
Safety and tolerability of once daily dosing of 590 mg Liposomal Amikacin for Inhalation (LAI) added to a multi-drug regimen in participants with non-tuberculous mycobacterium (NTM) lung infections due to Mycobacterium avium complex (MAC) who are refractory to therapy and failed to convert in Study INS-212. Participants participating in Study INS-212 who had not achieved the INS-212 protocol definition of culture conversion (3 consecutive monthly negative sputum cultures) or who had experienced a relapse or recurrence (agar positive or more than 2 consecutive broth positive results after culture conversion had occurred) by Month 6, as determined by their sputum culture results from Day 1 through Month 6 and confirmed at their scheduled Month 8 visit, were eligible to participate in Study INS-312. For participants who chose to participate in Study INS-312, the Month 8 visit of Study INS-212 became their end of treatment (EOT) visit; these participants were then asked to provide written informed consent for Study INS-312 and were enrolled directly into Study INS-312 after having met all eligibility criteria. Participants in Study INS-212 had either received 590 mg LAI plus an MDR (LAI + MDR arm) or a multidrug regimen alone (MDR alone arm). All participants in this safety extension study were to continue the multidrug antimycobacterial regimen that they were receiving during Study INS-212 and will receive LAI 590 mg administered daily (QD) for up to 12 months. The participants will remain in the study for up to a total of 13 months (up to 12 months on-treatment plus 1 month off LAI treatment for safety follow up).
Interventions
DRUGLAI 590 mg
LAI 590 mg QD: administered by inhaling drug product that had been aerosolized in an investigational eFlow nebulizer over approximately 14 minutes
DRUGMulti-drug regimen
Multidrug antimycobacterial regimen from study INS-212
Sponsors
Insmed Incorporated
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. had successfully completed the Month 6 and End of Treatment visits in Study INS-212 2. had not achieved the INS-212 protocol definition of culture conversion by Month 6 in Study INS-212 OR had experienced a relapse or recurrence by Month 6 in Study INS-212. Key
Exclusion criteria
1\. achieved culture conversion without relapse or recurrence in the Study INS-212 study by Month 6
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From baseline to 28 days after end of treatment, up to 13 months | TEAEs are defined as those AEs that occurred on or after the date of first dose of study medication in INS-312 and within 28 days after the last dose. If it couldn't be determined whether the AE is treatment emergent due to a partial onset date, then it was classified as treatment emergent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Culture Conversion by Month 6 and Month 12 | by Month 6 and Month 12 | 6 months: Converters are defined as participants who had 3 consecutive monthly MAC-negative sputum cultures by Month 6 (last opportunity to convert was at Month 4). 12 months: Converters are defined as participants who had 3 consecutive monthly MAC-negative sputum cultures by Month 12 (last opportunity to convert was at Month 10). |
| Time to Culture Conversion | by Month 12 | The time to culture conversion is defined as the date of conversion for participants achieving culture conversion is defined as the date of the first of 3-consecutive monthly negative sputum cultures. Then, the number of days to culture conversion is defined as the difference between the date of conversion and the date of first dose of LAI. |
| Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | From baseline to Month 12 or end of treatment | A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and Month 6 and Month 12/EOT. The standardized protocol based on the American Thoracic Society (ATS) guidelines (http://doi.org/10.1164/ajrccm.166.1.at1102) was used. After assessments were performed for heart rate, blood pressure, pulse oximetry (SpO2), dyspnea, and overall fatigue using the Borg scale, participants were instructed to walk on a prescribed course as far as they could in 6 minutes. Pre-test assessment parameters were repeated after exertion. The maximum distance achieved and post exertion heart rate and SpO2 were compared to pre-test values. The maximum distance achieved was recorded in the electronic case report form. |
Participant flow
Pre-assignment details
Participants in Study INS-212 had either received 590 mg LAI plus an MDR (LAI + MDR arm) or a multidrug regimen alone (MDR alone arm). All participants in this safety extension study, INS-312, were to continue the multidrug antimycobacterial regimen that they were receiving during Study INS-212 and received LAI 590 mg QD for up to 12 months.
Participants by arm
| Arm | Count |
|---|---|
| Prior LAI + Multidrug Regimen Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | 73 |
| Prior Multidrug Regimen Alone Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. | 90 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 20 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other not specified | 1 | 0 |
| Overall Study | Physician Decision | 2 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 8 |
Baseline characteristics
| Characteristic | Prior Multidrug Regimen Alone | Total | Prior LAI + Multidrug Regimen |
|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 10.33 | 64.8 years STANDARD_DEVIATION 9.78 | 64.9 years STANDARD_DEVIATION 9.12 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 22 Participants | 50 Participants | 28 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 1 Participants |
| Race (NIH/OMB) White | 60 Participants | 101 Participants | 41 Participants |
| Sex: Female, Male Female | 54 Participants | 105 Participants | 51 Participants |
| Sex: Female, Male Male | 36 Participants | 58 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 73 | 4 / 90 |
| other Total, other adverse events | 45 / 73 | 75 / 90 |
| serious Total, serious adverse events | 20 / 73 | 32 / 90 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
TEAEs are defined as those AEs that occurred on or after the date of first dose of study medication in INS-312 and within 28 days after the last dose. If it couldn't be determined whether the AE is treatment emergent due to a partial onset date, then it was classified as treatment emergent.
Time frame: From baseline to 28 days after end of treatment, up to 13 months
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 Serious TEAE (sTEAE) | 20 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE Leading to MDR for NTM withdrawn | 4 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 Treatment-emergent AE (TEAE) | 68 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE leading to study drug withdrawn | 8 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TE AE Leading to LAI withdrawn | 6 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE Leading to LAI and MDR for NTM withdrawn | 1 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 sTEAE leading to LAI withdrawn | 3 participants |
| Prior LAI + Multidrug Regimen | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE leading to death | 2 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE leading to death | 4 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 Serious TEAE (sTEAE) | 32 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TE AE Leading to LAI withdrawn | 22 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE Leading to MDR for NTM withdrawn | 8 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 sTEAE leading to LAI withdrawn | 9 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 Treatment-emergent AE (TEAE) | 90 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE Leading to LAI and MDR for NTM withdrawn | 5 participants |
| Prior Multidrug Regimen Alone | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ≥1 TEAE leading to study drug withdrawn | 24 participants |
Secondary
Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance
A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and Month 6 and Month 12/EOT. The standardized protocol based on the American Thoracic Society (ATS) guidelines (http://doi.org/10.1164/ajrccm.166.1.at1102) was used. After assessments were performed for heart rate, blood pressure, pulse oximetry (SpO2), dyspnea, and overall fatigue using the Borg scale, participants were instructed to walk on a prescribed course as far as they could in 6 minutes. Pre-test assessment parameters were repeated after exertion. The maximum distance achieved and post exertion heart rate and SpO2 were compared to pre-test values. The maximum distance achieved was recorded in the electronic case report form.
Time frame: From baseline to Month 12 or end of treatment
Population: Baseline: number of participants with data at this visit.~Change from baseline: number of participants with both baseline and 6 month scores.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Prior LAI + Multidrug Regimen | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | Change from Baseline to Month 12 | -10.1 meters | Standard Deviation 79.23 |
| Prior LAI + Multidrug Regimen | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | Baseline | 435.9 meters | Standard Deviation 132.33 |
| Prior LAI + Multidrug Regimen | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | Change from Baseline to Month 6 | -10.4 meters | Standard Deviation 69.77 |
| Prior Multidrug Regimen Alone | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | Baseline | 449.0 meters | Standard Deviation 122.64 |
| Prior Multidrug Regimen Alone | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | Change from Baseline to Month 6 | -20.8 meters | Standard Deviation 51.57 |
| Prior Multidrug Regimen Alone | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | Change from Baseline to Month 12 | -42.2 meters | Standard Deviation 72.66 |
Secondary
Number of Participants Achieving Culture Conversion by Month 6 and Month 12
6 months: Converters are defined as participants who had 3 consecutive monthly MAC-negative sputum cultures by Month 6 (last opportunity to convert was at Month 4). 12 months: Converters are defined as participants who had 3 consecutive monthly MAC-negative sputum cultures by Month 12 (last opportunity to convert was at Month 10).
Time frame: by Month 6 and Month 12
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prior LAI + Multidrug Regimen | Number of Participants Achieving Culture Conversion by Month 6 and Month 12 | 6 months | 7 Participants |
| Prior LAI + Multidrug Regimen | Number of Participants Achieving Culture Conversion by Month 6 and Month 12 | 12 months | 10 Participants |
| Prior Multidrug Regimen Alone | Number of Participants Achieving Culture Conversion by Month 6 and Month 12 | 6 months | 24 Participants |
| Prior Multidrug Regimen Alone | Number of Participants Achieving Culture Conversion by Month 6 and Month 12 | 12 months | 30 Participants |
Secondary
Time to Culture Conversion
The time to culture conversion is defined as the date of conversion for participants achieving culture conversion is defined as the date of the first of 3-consecutive monthly negative sputum cultures. Then, the number of days to culture conversion is defined as the difference between the date of conversion and the date of first dose of LAI.
Time frame: by Month 12
Population: The Safety population was the set of all enrolled participants who received at least 1 dose of LAI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prior LAI + Multidrug Regimen | Time to Culture Conversion | NA months |
| Prior Multidrug Regimen Alone | Time to Culture Conversion | NA months |