Open-label Safety Extension Study Assessing Safety and Tolerability of LAI in Patients Who Participated in Study INS-212

• Sponsor: Insmed Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02628600
• Collaborator: (none)
• Enrollment: 163
• Arms: 2
• Actual Duration (Months): 32.4

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
NTM Lung Infection Due to MAC	Drug: LAI 590 mg; Drug: Multi-drug regimen	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

• Study Type: Interventional
• Actual Enrollment: 163 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Safety Extension Study to a Multicenter Study of Liposomal Amikacin for Inhalation (LAI) in Adult Patients With Nontuberculous Mycobacterial (NTM) Lung Infections Caused by Mycobacterium Avium Complex (MAC) That Are Refractory to Treatment
• Actual Study Start Date: Feb 5, 2016
• Actual Primary Completion Date: Oct 17, 2018
• Actual Study Completion Date: Oct 17, 2018

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: Amikacin Liposome Inhalation Suspension (ALIS) ARIKAYCE® ; 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: Amikacin Liposome Inhalation Suspension (ALIS) ARIKAYCE® ; Drug: Multi-drug regimen; Multidrug antimycobacterial regimen from study INS-212

Outcome Measures

Primary Outcome Measures

1. 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

1. 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).

2. 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.

3. 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

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Insmed Incorporated

Investigators

• Study Director: Kevin Mange, MD, Insmed Incorporated

Study Documents (Full-Text)

• Statistical Analysis Plan - Nov 13, 2018
• Study Protocol - May 25, 2017

More Information

Publications

None provided.

• Responsible Party: Insmed Incorporated
• ClinicalTrials.gov Identifier: NCT02628600
• Other Study ID Numbers: INS-312; 2015-003170-33
• First Posted: Dec 11, 2015
• Last Update Posted: Feb 10, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by Insmed Incorporated: ALIS; ARIKAYCE
• Additional relevant MeSH terms: Infections; Amikacin

Study Results

Participant Flow

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

1. Primary Outcome

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%

2. Secondary Outcome

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%

3. Secondary Outcome

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

4. Secondary Outcome

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
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

[Not Specified]

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.