Trial Outcomes & Findings for Open-label Safety Extension Study Assessing Safety and Tolerability of LAI in Patients Who Participated in Study INS-212 (NCT NCT02628600)

Last Updated: 2020-02-10

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

163 participants

Primary outcome timeframe

From baseline to 28 days after end of treatment, up to 13 months

Results posted on

2020-02-10

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	73	90
Overall Study Participant Discontinued the Study	24	32
Overall Study COMPLETED	49	58
Overall Study NOT COMPLETED	24	32

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Death	2	1
Overall Study Adverse Event	3	20
Overall Study Protocol Violation	0	1
Overall Study Lack of Efficacy	2	0
Overall Study Withdrawal by Subject	13	8
Overall Study Lost to Follow-up	1	0
Overall Study Physician Decision	2	2
Overall Study Other not specified	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Prior LAI + Multidrug Regimen n=73 Participants Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 Participants Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.	Total n=163 Participants Total of all reporting groups
Age, Continuous	64.9 years STANDARD_DEVIATION 9.12 • n=5 Participants	64.8 years STANDARD_DEVIATION 10.33 • n=7 Participants	64.8 years STANDARD_DEVIATION 9.78 • n=5 Participants
Sex: Female, Male Female	51 Participants n=5 Participants	54 Participants n=7 Participants	105 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants	36 Participants n=7 Participants	58 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	28 Participants n=5 Participants	22 Participants n=7 Participants	50 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) White	41 Participants n=5 Participants	60 Participants n=7 Participants	101 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline to 28 days after end of treatment, up to 13 months

Population: Safety population

Outcome measures

Outcome measures
Measure	Prior LAI + Multidrug Regimen n=73 Participants Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 Participants Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 Treatment-emergent AE (TEAE)	68 participants	90 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 TEAE Leading to MDR for NTM withdrawn	4 participants	8 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 TEAE Leading to LAI and MDR for NTM withdrawn	1 participants	5 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 TEAE leading to death	2 participants	4 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 Serious TEAE (sTEAE)	20 participants	32 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 TEAE leading to study drug withdrawn	8 participants	24 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 TE AE Leading to LAI withdrawn	6 participants	22 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ≥1 sTEAE leading to LAI withdrawn	3 participants	9 participants

SECONDARY outcome

Timeframe: by Month 6 and Month 12

Population: Safety population

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).

Outcome measures

Outcome measures
Measure	Prior LAI + Multidrug Regimen n=73 Participants Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 Participants Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
Number of Participants Achieving Culture Conversion by Month 6 and Month 12 6 months	7 Participants	24 Participants
Number of Participants Achieving Culture Conversion by Month 6 and Month 12 12 months	10 Participants	30 Participants

SECONDARY outcome

Timeframe: by Month 12

Population: The Safety population was the set of all enrolled participants who received at least 1 dose of LAI.

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.

Outcome measures

Outcome measures
Measure	Prior LAI + Multidrug Regimen n=73 Participants Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 Participants Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
Time to Culture Conversion	NA months Not able to be estimated due to an insufficient number of participants achieving conversion	NA months Not able to be estimated due to an insufficient number of participants achieving conversion

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Prior LAI + Multidrug Regimen n=73 Participants Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 Participants Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
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	-20.8 meters Standard Deviation 51.57
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	-42.2 meters Standard Deviation 72.66
Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance Baseline	435.9 meters Standard Deviation 132.33	449.0 meters Standard Deviation 122.64

Adverse Events

Prior LAI + Multidrug Regimen

Serious events: 20 serious events

Other events: 45 other events

Deaths: 2 deaths

Prior Multidrug Regimen Alone

Serious events: 32 serious events

Other events: 75 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Prior LAI + Multidrug Regimen n=73 participants at risk Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 participants at risk Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
Gastrointestinal disorders Diarrhoea	5.5% 4/73 • Number of events 5 • From baseline up to 28 days after end of treatment, up to 13 months	10.0% 9/90 • Number of events 11 • From baseline up to 28 days after end of treatment, up to 13 months
Gastrointestinal disorders Nausea	6.8% 5/73 • Number of events 6 • From baseline up to 28 days after end of treatment, up to 13 months	10.0% 9/90 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months
General disorders Fatigue	4.1% 3/73 • Number of events 3 • From baseline up to 28 days after end of treatment, up to 13 months	14.4% 13/90 • Number of events 13 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Nasopharyngitis	13.7% 10/73 • Number of events 11 • From baseline up to 28 days after end of treatment, up to 13 months	7.8% 7/90 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Infective exacerbation of bronchiectasis	8.2% 6/73 • Number of events 7 • From baseline up to 28 days after end of treatment, up to 13 months	11.1% 10/90 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months
Investigations Weight decreased	9.6% 7/73 • Number of events 7 • From baseline up to 28 days after end of treatment, up to 13 months	8.9% 8/90 • Number of events 8 • From baseline up to 28 days after end of treatment, up to 13 months
Renal and urinary disorders Haematuria	5.5% 4/73 • Number of events 4 • From baseline up to 28 days after end of treatment, up to 13 months	5.6% 5/90 • Number of events 6 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Dysphonia	6.8% 5/73 • Number of events 6 • From baseline up to 28 days after end of treatment, up to 13 months	43.3% 39/90 • Number of events 54 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Cough	12.3% 9/73 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months	35.6% 32/90 • Number of events 37 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.3% 9/73 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months	17.8% 16/90 • Number of events 17 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Haemoptysis	13.7% 10/73 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months	10.0% 9/90 • Number of events 10 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Productive cough	5.5% 4/73 • Number of events 5 • From baseline up to 28 days after end of treatment, up to 13 months	6.7% 6/90 • Number of events 6 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.7% 2/73 • Number of events 2 • From baseline up to 28 days after end of treatment, up to 13 months	7.8% 7/90 • Number of events 8 • From baseline up to 28 days after end of treatment, up to 13 months

Additional Information

Kevin Mange (Senior Vice President, Clinical Development & Medical Affairs, ALIS)

Insmed Inc

Phone: 908-947-2651

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Prior LAI + Multidrug Regimen n=73 participants at risk Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR.	Prior Multidrug Regimen Alone n=90 participants at risk Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Nervous system disorders Cerebral infarction	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Nervous system disorders Neuropathy peripheral	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Nervous system disorders Transient ischaemic attack	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Alveolitis allergic	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.7% 2/73 • From baseline up to 28 days after end of treatment, up to 13 months	4.4% 4/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Cardiac disorders Atrial fibrillation	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	2.2% 2/90 • From baseline up to 28 days after end of treatment, up to 13 months
Eye disorders Cataract	2.7% 2/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Eye disorders Vision blurred	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Gastrointestinal disorders Ascites	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Gastrointestinal disorders Gastritis	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
General disorders Asthenia	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
General disorders Chest pain	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
General disorders Performance status decreased	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Bronchopulmonary aspergillosis allergic	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Gastroenteritis viral	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Infective exacerbation of bronchiectasis	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	3.3% 3/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Laryngitis	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Lower respiratory tract infection	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Mycobacterium abscessus infection	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Mycobacterium avium complex infection	2.7% 2/73 • From baseline up to 28 days after end of treatment, up to 13 months	5.6% 5/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Pneumonia	4.1% 3/73 • From baseline up to 28 days after end of treatment, up to 13 months	4.4% 4/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Pneumonia fungal	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Post procedural pneumonia	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Respiratory tract infection	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Infections and infestations Sinobronchitis	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Injury, poisoning and procedural complications Hip fracture	2.7% 2/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Injury, poisoning and procedural complications Pelvic fracture	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Injury, poisoning and procedural complications Radius fracture	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Metabolism and nutrition disorders Dehydration	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Musculoskeletal and connective tissue disorders Back pain	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	0.00% 0/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Dyspnoea at rest	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.4% 1/73 • From baseline up to 28 days after end of treatment, up to 13 months	2.2% 2/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Lung infiltration	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	2.2% 2/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	2.2% 2/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	1.1% 1/90 • From baseline up to 28 days after end of treatment, up to 13 months
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/73 • From baseline up to 28 days after end of treatment, up to 13 months	2.2% 2/90 • From baseline up to 28 days after end of treatment, up to 13 months