Open-label Safety Extension Study Assessing Safety and Tolerability of LAI in Patients Who Participated in Study INS-212
Study Details
Study Description
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).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 3 |
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).
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: 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. |
Drug: LAI 590 mg
LAI 590 mg QD: administered by inhaling drug product that had been aerosolized in an investigational eFlow nebulizer over approximately 14 minutes
Other Names:
Drug: Multi-drug regimen
Multidrug antimycobacterial regimen from study INS-212
|
Experimental: 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. |
Drug: LAI 590 mg
LAI 590 mg QD: administered by inhaling drug product that had been aerosolized in an investigational eFlow nebulizer over approximately 14 minutes
Other Names:
Drug: Multi-drug regimen
Multidrug antimycobacterial regimen from study INS-212
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Key Inclusion Criteria:
-
had successfully completed the Month 6 and End of Treatment visits in Study INS-212
-
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:
- achieved culture conversion without relapse or recurrence in the Study INS-212 study by Month 6
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Insmed Incorporated
Investigators
- Study Director: Kevin Mange, MD, Insmed Incorporated
Study Documents (Full-Text)
More Information
Publications
None provided.- INS-312
- 2015-003170-33
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | 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. |
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone |
---|---|---|
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. |
Period Title: Overall Study | ||
STARTED | 73 | 90 |
Participant Discontinued the Study | 24 | 32 |
COMPLETED | 49 | 58 |
NOT COMPLETED | 24 | 32 |
Baseline Characteristics
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone | Total |
---|---|---|---|
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. | Total of all reporting groups |
Overall Participants | 73 | 90 | 163 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
64.9
(9.12)
|
64.8
(10.33)
|
64.8
(9.78)
|
Sex: Female, Male (Count of Participants) | |||
Female |
51
69.9%
|
54
60%
|
105
64.4%
|
Male |
22
30.1%
|
36
40%
|
58
35.6%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
Asian |
28
38.4%
|
22
24.4%
|
50
30.7%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
2
2.7%
|
3
3.3%
|
5
3.1%
|
White |
41
56.2%
|
60
66.7%
|
101
62%
|
More than one race |
1
1.4%
|
0
0%
|
1
0.6%
|
Unknown or Not Reported |
1
1.4%
|
5
5.6%
|
6
3.7%
|
Outcome Measures
Title | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Safety population |
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone |
---|---|---|
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. |
Measure Participants | 73 | 90 |
≥1 Treatment-emergent AE (TEAE) |
68
93.2%
|
90
100%
|
≥1 Serious TEAE (sTEAE) |
20
27.4%
|
32
35.6%
|
≥1 TEAE leading to study drug withdrawn |
8
11%
|
24
26.7%
|
≥1 TE AE Leading to LAI withdrawn |
6
8.2%
|
22
24.4%
|
≥1 TEAE Leading to MDR for NTM withdrawn |
4
5.5%
|
8
8.9%
|
≥1 TEAE Leading to LAI and MDR for NTM withdrawn |
1
1.4%
|
5
5.6%
|
≥1 sTEAE leading to LAI withdrawn |
3
4.1%
|
9
10%
|
≥1 TEAE leading to death |
2
2.7%
|
4
4.4%
|
Title | Number of Participants Achieving Culture Conversion by Month 6 and Month 12 |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Safety population |
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone |
---|---|---|
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. |
Measure Participants | 73 | 90 |
6 months |
7
9.6%
|
24
26.7%
|
12 months |
10
13.7%
|
30
33.3%
|
Title | Time to Culture Conversion |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
The Safety population was the set of all enrolled participants who received at least 1 dose of LAI. |
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone |
---|---|---|
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. |
Measure Participants | 73 | 90 |
Median (Full Range) [months] |
NA
|
NA
|
Title | Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Baseline: number of participants with data at this visit. Change from baseline: number of participants with both baseline and 6 month scores. |
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone |
---|---|---|
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. |
Measure Participants | 73 | 90 |
Baseline |
435.9
(132.33)
|
449.0
(122.64)
|
Change from Baseline to Month 6 |
-10.4
(69.77)
|
-20.8
(51.57)
|
Change from Baseline to Month 12 |
-10.1
(79.23)
|
-42.2
(72.66)
|
Adverse Events
Time Frame | From baseline up to 28 days after end of treatment, up to 13 months | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone | ||
Arm/Group Description | Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. | ||
All Cause Mortality |
||||
Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/73 (2.7%) | 4/90 (4.4%) | ||
Serious Adverse Events |
||||
Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 20/73 (27.4%) | 32/90 (35.6%) | ||
Cardiac disorders | ||||
Atrial fibrillation | 1/73 (1.4%) | 2/90 (2.2%) | ||
Eye disorders | ||||
Cataract | 2/73 (2.7%) | 0/90 (0%) | ||
Vision blurred | 0/73 (0%) | 1/90 (1.1%) | ||
Gastrointestinal disorders | ||||
Ascites | 0/73 (0%) | 1/90 (1.1%) | ||
Gastritis | 0/73 (0%) | 1/90 (1.1%) | ||
General disorders | ||||
Asthenia | 1/73 (1.4%) | 0/90 (0%) | ||
Chest pain | 1/73 (1.4%) | 0/90 (0%) | ||
Performance status decreased | 0/73 (0%) | 1/90 (1.1%) | ||
Infections and infestations | ||||
Bronchopulmonary aspergillosis allergic | 0/73 (0%) | 1/90 (1.1%) | ||
Gastroenteritis viral | 1/73 (1.4%) | 0/90 (0%) | ||
Infective exacerbation of bronchiectasis | 1/73 (1.4%) | 3/90 (3.3%) | ||
Laryngitis | 0/73 (0%) | 1/90 (1.1%) | ||
Lower respiratory tract infection | 1/73 (1.4%) | 0/90 (0%) | ||
Mycobacterium abscessus infection | 1/73 (1.4%) | 0/90 (0%) | ||
Mycobacterium avium complex infection | 2/73 (2.7%) | 5/90 (5.6%) | ||
Pneumonia | 3/73 (4.1%) | 4/90 (4.4%) | ||
Pneumonia fungal | 0/73 (0%) | 1/90 (1.1%) | ||
Post procedural pneumonia | 0/73 (0%) | 1/90 (1.1%) | ||
Respiratory tract infection | 1/73 (1.4%) | 0/90 (0%) | ||
Sinobronchitis | 0/73 (0%) | 1/90 (1.1%) | ||
Injury, poisoning and procedural complications | ||||
Hip fracture | 2/73 (2.7%) | 0/90 (0%) | ||
Pelvic fracture | 0/73 (0%) | 1/90 (1.1%) | ||
Radius fracture | 1/73 (1.4%) | 0/90 (0%) | ||
Metabolism and nutrition disorders | ||||
Dehydration | 1/73 (1.4%) | 0/90 (0%) | ||
Musculoskeletal and connective tissue disorders | ||||
Back pain | 1/73 (1.4%) | 0/90 (0%) | ||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
Breast cancer | 0/73 (0%) | 1/90 (1.1%) | ||
Nervous system disorders | ||||
Cerebral infarction | 0/73 (0%) | 1/90 (1.1%) | ||
Neuropathy peripheral | 0/73 (0%) | 1/90 (1.1%) | ||
Transient ischaemic attack | 1/73 (1.4%) | 0/90 (0%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Acute respiratory failure | 0/73 (0%) | 1/90 (1.1%) | ||
Alveolitis allergic | 1/73 (1.4%) | 0/90 (0%) | ||
Chronic obstructive pulmonary disease | 2/73 (2.7%) | 4/90 (4.4%) | ||
Dyspnoea | 0/73 (0%) | 1/90 (1.1%) | ||
Dyspnoea at rest | 0/73 (0%) | 1/90 (1.1%) | ||
Haemoptysis | 1/73 (1.4%) | 2/90 (2.2%) | ||
Hypoxia | 0/73 (0%) | 1/90 (1.1%) | ||
Interstitial lung disease | 0/73 (0%) | 1/90 (1.1%) | ||
Lung infiltration | 0/73 (0%) | 1/90 (1.1%) | ||
Pneumothorax | 0/73 (0%) | 2/90 (2.2%) | ||
Pulmonary embolism | 0/73 (0%) | 2/90 (2.2%) | ||
Pulmonary fibrosis | 0/73 (0%) | 1/90 (1.1%) | ||
Respiratory failure | 0/73 (0%) | 2/90 (2.2%) | ||
Other (Not Including Serious) Adverse Events |
||||
Prior LAI + Multidrug Regimen | Prior Multidrug Regimen Alone | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 45/73 (61.6%) | 75/90 (83.3%) | ||
Gastrointestinal disorders | ||||
Diarrhoea | 4/73 (5.5%) | 5 | 9/90 (10%) | 11 |
Nausea | 5/73 (6.8%) | 6 | 9/90 (10%) | 10 |
General disorders | ||||
Fatigue | 3/73 (4.1%) | 3 | 13/90 (14.4%) | 13 |
Infections and infestations | ||||
Nasopharyngitis | 10/73 (13.7%) | 11 | 7/90 (7.8%) | 10 |
Infective exacerbation of bronchiectasis | 6/73 (8.2%) | 7 | 10/90 (11.1%) | 10 |
Investigations | ||||
Weight decreased | 7/73 (9.6%) | 7 | 8/90 (8.9%) | 8 |
Renal and urinary disorders | ||||
Haematuria | 4/73 (5.5%) | 4 | 5/90 (5.6%) | 6 |
Respiratory, thoracic and mediastinal disorders | ||||
Dysphonia | 5/73 (6.8%) | 6 | 39/90 (43.3%) | 54 |
Cough | 9/73 (12.3%) | 10 | 32/90 (35.6%) | 37 |
Dyspnoea | 9/73 (12.3%) | 10 | 16/90 (17.8%) | 17 |
Haemoptysis | 10/73 (13.7%) | 10 | 9/90 (10%) | 10 |
Productive cough | 4/73 (5.5%) | 5 | 6/90 (6.7%) | 6 |
Oropharyngeal pain | 2/73 (2.7%) | 2 | 7/90 (7.8%) | 8 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The PI agrees not to originate or use the name of Insmed Incorporated, or study drug code in any publicity, news release, or other public announcement, written or oral, whether to the public, press, or otherwise, relating to this protocol, to any amendment to the protocol, or to the performance of this protocol, without the prior written consent of Insmed Incorporated.
Results Point of Contact
Name/Title | Kevin Mange (Senior Vice President, Clinical Development & Medical Affairs, ALIS) |
---|---|
Organization | Insmed Inc |
Phone | 908-947-2651 |
kevin.mange@insmed.com |
- INS-312
- 2015-003170-33