E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nontuberculous Mycobacterial (NTM) Lung Infections caused by Mycobacterium avium complex (MAC) that are refractory to treatment |
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E.1.1.1 | Medical condition in easily understood language |
Nontuberculous Mycobacterial (NTM) Lung Infections caused by Mycobacterium avium complex (MAC) that are refractory to treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058806 |
E.1.2 | Term | Mycobacterium avium complex infection |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate long term safety and tolerability of LAI (590 mg) administered once daily (QD) for up to 12 months in subjects who were refractory to standard multi-drug treatment and failed to convert in Study INS-212. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives 1. To evaluate the number of subjects achieving culture conversion (3 consecutive monthly negative sputum cultures) by Month 12/EOT (end of treatment) 2. To evaluate the number of subjects achieving culture conversion by Month 6 3. To evaluate the time to culture conversion 4. To evaluate the change in the six-minute walk test (6MWT) distance at Month 6 and Month 12/EOT
Exploratory Objectives 1. To assess subject-reported symptoms of NTM and change from Baseline in quality of life scores on the St George’s Respiratory Questionnaire (SGRQ) and quality of life scores on the SGRQ – Part II (Activities of Daily Living) at Month 6 and Month 12/EOT 2. To assess the change from Baseline in the EQ-5D-3L questionnaire subject-reported health outcomes at Month 6 and Month 12/EOT |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study of INS-312: CT Scan Sub-Study CT Scan Sub-Study Protocol Version Date: 11 March 2016 |
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E.3 | Principal inclusion criteria |
Subjects are eligible to participate in the study if they meet all the following inclusion criteria:
1. have successfully completed the Month 6 and End of Treatment (EoT) visits in INS-212 2. have not achieved the INS-212 protocol definition of culture conversion (3 consecutive monthly negative sputum cultures) by Month 6 in INS-212 OR have experienced a relapse or recurrence (agar positive or more than 2 consecutive broth positive results after culture conversion has occurred) by Month 6 in INS-212 3. have demonstrated compliance with treatment regimen in INS-212, including LAI, if applicable 4. willing to adhere to multi-drug treatment regimen during the course of the study 5. female of child bearing potential agrees to practice an acceptable method of birth control (e.g., true abstinence [refraining from heterosexual intercourse during the entire study], hormonal or barrier methods, partner sterilization, or intrauterine device [IUD]) while participating in the trial. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), declaration of abstinence for the duration of the study, and withdrawal are not acceptable methods of contraception. 6. the subject will provide written informed consent 7. willing to have serum and sputum specimens stored 8. able to comply with study drug use, study visits, and study procedures as determined by the Investigator
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E.4 | Principal exclusion criteria |
Subjects are not eligible to participate in the study if they meet any of the following criteria:
1. achieved culture conversion without relapse or recurrence in the INS-212 study by Month 6 2. early discontinuation (prior to Month 6 study visit) from INS-212 3. met any of the exclusion criteria of the INS-212 study, with the exception of the following: a. unable to perform the 6MWT b. prior exposure to LAI (including clinical study) c. in the opinion of the Investigator, patients who are not expected to survive the duration of the study d. active allergic bronchopulmonary mycosis or any other condition requiring chronic systemic corticosteroids at a dose greater than the equivalent of 10 mg/day of prednisone e. initiation of chronic therapy (e.g., high dose ibuprofen, inhaled anti-inflammatory agents including steroids, low dose maintenance steroids, rhDNase) 4. positive pregnancy test or lactation. All women of child bearing potential will be tested. Women not of child bearing potential are defined as postmenopausal (i.e., amenorrheic for at least 1 year), or surgically or naturally sterile. 5. significant (as determined by the Investigator) hearing loss, vestibular dysfunction, or neuromuscular weakness where the potential risk of aminoglycoside toxicity outweighs the potential benefit 6. aspartate aminotransferase or alanine aminotransferase ≥ 3 times the upper limit of normal (ULN) and/or total bilirubin ≥ 2 times the ULN at their Month 6 study visit in INS-212 7. absolute neutrophil count ≤500/μL at their Month 6 study visit in INS-212 8. serum creatinine >2 times ULN at their Month 6 study visit in INS-212 9. current alcohol, medication abuse or illicit drug abuse 10. any condition that, in the opinion of the Investigator, interferes with ability to safely complete the study or adhere to study requirements 11. diagnosis of myasthenia gravis. |
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E.5 End points |
E.5.1 | Primary end point(s) |
PRIARY ENDPOINT - SAFETY The primary endpoint is the frequency of treatment-emergent adverse events (TEAEs), TEAEs leading to withdrawal from study, treatment-emergent serious adverse events (SAEs), AEs of special interest, clinically significant abnormal laboratory test results, and vital signs measurements. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline until end of study. |
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E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS - EFFICACY 1. Proportion of subjects achieving culture conversion (3 consecutive negative monthly sputum cultures without relapse or recurrence) by Month 12/EoT 2. Proportion of subjects achieving culture conversion by Month 6 3. Time to culture conversion. The date of conversion is defined by the date of the first of at least 3 consecutive monthly culture specimens that are MAC negative. 4. The mean change from Baseline in 6MWT distance at Month 6 and Month 12/EOT
EXPLORATORY ENDPOINTS - EFFICACY 1. The mean change from Baseline at Month 6 and Month 12/EOT in the overall SGRQ and SGRQ – Part II (Activities of Daily Living) 2. The mean change from Baseline at Month 6 and Month 12/EOT in the EQ 5D-3L 3. Radiological changes in CT scan at EoT, within a sub-set of subjects. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline until end of study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Canada |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
New Zealand |
Poland |
Spain |
Sweden |
Taiwan |
Thailand |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |