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    Summary
    EudraCT Number:2014-005010-31
    Sponsor's Protocol Code Number:INS-212
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-02-26
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2014-005010-31
    A.3Full title of the trial
    A Randomized, Open Label, 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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Open Label, Multicenter Study of Liposomal Amikacin for Inhalation in Adult Patients who have Nontuberculous Mycobacterial Lung Infections caused by Mycobacterium avium complex that are refractory to treatment
    A.4.1Sponsor's protocol code numberINS-212
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02344004
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInsmed Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportInsmed Incorporated
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationInsmed Inc.
    B.5.2Functional name of contact pointTom Vanthienen
    B.5.3 Address:
    B.5.3.1Street Address10 Finderne Avenue, Building 10
    B.5.3.2Town/ cityBridgewater
    B.5.3.3Post codeNJ 08807 3365
    B.5.3.4CountryUnited States
    B.5.4Telephone number+41795432860
    B.5.5Fax number+19085264047
    B.5.6E-mailtom.vanthienen@insmed.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1259
    D.3 Description of the IMP
    D.3.1Product nameLiposomal Amikacin for Inhalation (LAI)
    D.3.4Pharmaceutical form Nebuliser suspension
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAMIKACIN SULFATE
    D.3.9.1CAS number 39831-55-5
    D.3.9.3Other descriptive nameAmikacin Sulfate
    D.3.9.4EV Substance CodeSUB00444MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number70
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Nontuberculous Mycobacterial (NTM) Lung Infections caused by Mycobacterium avium complex (MAC) that are refractory to treatment
    E.1.1.1Medical condition in easily understood language
    Nontuberculous Mycobacterial (NTM) Lung Infections caused by Mycobacterium avium complex (MAC) that are refractory to treatment
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10058806
    E.1.2Term Mycobacterium avium complex infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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 the 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.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.3Principal 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, 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 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
    E.4Principal 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 child bearing 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. HIV-positive 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.5.1Primary end point(s)
    The primary endpoint is the proportion of subjectsachieving culture conversion (3 consecutive monthly negative sputum cultures) by Month 6 in the LAI arm compared to multi-drug regimen alone.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation of primary endpoint will be done at Month 8
    E.5.2Secondary 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
    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 nonconverters 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
    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 Month 6 and EOT in the EQ 5D-3L
    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.5.2.1Timepoint(s) of evaluation of this end point
    From baseline till end of study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 75
    F.4.2.2In the whole clinical trial 351
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At Month8, all non-converters will be eligible to enter a separate open-label study. All converters will continue on the same treatment regimen until they complete a total of 12 months beginning from the first negative culture.
    The investigator will discuss treatment options with each subjects.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-05-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-04-09
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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