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 | 19.1 |
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 |
|
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 the efficacy of LAI (590 mg) administered once daily (QD), when added to a multi-drug regimen, for achieving culture conversion (3 consecutive monthly negative sputum cultures) by Month 6 compared to a multi-drug regimen alone |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of LAI administered QD.
1. ..when added to a multi drug regimen on the 6MWT at Month 6
compared to a multi-drug regimen alone
2. ..when added to a multi-drug regimen on durability of treatment success 3 months after the end of total treatment course (negative sputum culture after 3 months off-treatment)
3. ..when added to a multi drug regimen for time to culture conversion compared to a multi-drug regimen alone
4. ..when added to a multi-drug regimen, for achieving sustainability
(consecutive monthly negative sputum cultures [with no more than 2 consecutive broth positive cultures] for 12 months on treatment) compared to a multi-drug regimen alone
5. .. when added to a multi drug-regimen on the 6MWT at EOT compared to a multi-drug regimen alone
6. To evaluate patient-reported symptoms of NTM and change from
Baseline in quality of life scores on the SGRQ at Month 6
For exploratory, safety &pharmacokinetic objectives please refer to protocol synopsis |
|
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 212:
CT Scan Sub-Study
CT Scan Sub-Study Protocol
Version Date: 22 February 2016
Sub-study of INS-212:
Comprehensive Pharmacokinetic Sub-Study (Japan)
Japanese Sub-Study Protocol
Version Date: 22 February 2016
Sub-study of INS 212:
Japan specific CT Scan Sub-Study
CT Scan Sub-Study Protocol
Version Date: 22 February 2016 |
|
E.3 | Principal inclusion criteria |
1. be male or female, 18 years or older (20 years or older in Japan)
2.be positive for MAC on culture as defined in inclusion criterion No. 4
while being treated with a multi-drug treatment regimen (at least 2
antibiotics) for a minimum duration of 6 consecutive months that is
either ongoing or was stopped no more than 12 months before Screening
(exceptions to multi-drug treatment regimen for 6 consecutive months
include treatment with doses or frequencies below those recommended
by guidelines and/or short interruptions of therapy, both occurring due
to safety/tolerability issues)
3. be diagnosed with MAC NTM lung infection with evidence of
underlying lung disease such as nodular bronchiectasis and/or
fibrocavitary disease by chest radiography (CXR) or high-resolution
chest computed tomography. High resolution CT (HRCT) scan is preferred, if available.
4. have a MAC lung infection documented by at least 2 positive cultures
(MAC or mixed infection with MAC as the dominant species), consisting
of at least one positive culture obtained within 6 months prior to
Screening and one positive culture at Screening (cultures to be at least 1
month apart). Cultures may be obtained from sputum or bronchoscopy.
5. have a MAC-positive sputum at screening
6. be willing to adhere to multi-drug treatment regimen during the course of the study
7. be able to produce approximately 3 mL of sputum or be willing to
undergo an induction that produces approximately 3 mL of sputum for mycobacteriology
8. 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, post-ovulation methods), declaration of abstinence for the duration of the study, and withdrawal are not acceptable methods of contraception.
9. the patient will provide written informed consent before performing any study related procedure
10. be willing to have serum specimens stored
11. be 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 |
1. patients with cystic fibrosis
2. patients whose MAC NTM infection is resistant to amikacin (as identified by MIC susceptibility >64 μg/ml)
3. patients who are not able to perform the 6MWT
4. positive pregnancy test or lactation at screening. All women of child bearing potential will be tested. Women not of childbearing potential are defined as postmenopausal (i.e., amenorrheic for at least 1 year), or surgically or naturally sterile.
5. active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within 1 year before screening or anticipated during the study period
6. 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 within 3 months before screening
7. active pulmonary tuberculosis requiring treatment at screening
8. history of lung transplantation
9. initiation of chronic therapy (e.g., high-dose ibuprofen, inhaled anti-inflammatory agents including steroids, low dose maintenance steroids, recombinant human deoxyribonuclease [rhDNase]) within 28 days before Day 1.
10. administration of any investigational drug within 8 weeks before screening
11. prior exposure to LAI (including clinical study).
12. known hypersensitivity to aminoglycosides
13. use of inhaled or systemic aminoglycosides with activity against MAC (e.g., amikacin, kanamycin, or streptomycin) within 28 days before Day 1
14. acquired and primary immunodeficiency syndromes (e.g. HIVpositive
patients regardless of CD4 counts)
15. significant (as determined by the Investigator) hearing loss,
vestibular dysfunction, neuromuscular weakness or a diagnosis of
myasthenia gravis where the potential risk of aminoglycoside toxicity
outweighs the potential benefit
16. aspartate aminotransferase or alanine aminotransferase ≥ 3 times the upper limit of normal (ULN) or total bilirubin ≥ 2 times the upper limit of normal (ULN) at screening
17. absolute neutrophil count ≤500/μL at screening
18. serum creatinine >2 times ULN at screening
19. current alcohol, medication or illicit drug abuse
20. any condition that, in the opinion of the Investigator, interferes with ability to safely complete the study or adhere to study requirements
21. persons who have been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
22. in the opinion of the Investigator, patients who are not expected to
survive the duration of the study
23. patients with disseminated MAC infection |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjectsachieving culture conversion (3 consecutive monthly negative sputum cultures collected monthly without relapse or recurrence) by Month 6 in the LAI arm compared to multi-drug regimen alone. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of primary endpoint will be done at Month 8 |
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E.5.2 | Secondary end point(s) |
SECONDARY EFFICACY ENDPOINTS
1. Change in 6MWT distance at Month 6 in the LAI arm compared to a
multi drug regimen alone
2. Proportion of subjects achieving culture conversion with durability
after 3 months off treatment in the LAI arm compared to a multi drug
regimen alone in all evaluable subjects
3. Time to culture conversion in the LAI arm compared to a multi drug
regimen alone by Month 6
4. Proportion of subjects achieving culture conversion with sustainability at the EOT in the LAI arm compared to a multi-drug regimen alone
5. Change in 6MWT distance at EOT in the LAI arm compared to a multidrug regimen alone
6. Change from Baseline (Day 1) at Month 6 in the SGRQ.
EXPLORATORY ENDPOINTS
1. Change in 6MWT distance at Month 6 for converters versus non-converters in LAI arm
2. Change in 6MWT distance at Month 6 for converters versus non-converters for all subjects
3. Change in 6MWT distance at Month 6 for converters versus nonconverters in the multi-drug regimen alone arm
4. Change in BMI at Month 6 in LAI arm compared to a multi drug
regimen alone
5. Change in 6MWT distance at Month 8 and 3 months off-treatment in the LAI arm compared to a multi drug regimen alone
6. Proportion of subjects achieving culture conversion with durability
after 12 months off treatment (EOS) in the LAI arm compared to a multi drug regimen alone in all evaluable subjects
7. Change from baseline (Day 1) at Month 6 in the SGRQ – Part 2
(Activities of Daily Livings)
8. Change from baseline (Day 1) at EOT in the EQ 5D
9. Proportion of subjects who develop a new strain of MAC in the LAI
arm compared to multi-drug regimen alone
10. Radiological changes in chest CT Scan at EOT in the LAI arm
compared to multi-drug regimen alone, in a sub-set of subjects
11. Mortality at EOS. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline till end of study |
|
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 | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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
|
|
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 | 9 |
E.8.9.1 | In the Member State concerned days | 21 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 7 |