E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic Fibrosis subjects with chronic Burkholderia spp. infection of the airways. |
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E.1.1.1 | Medical condition in easily understood language |
Cystic Fibrosis with an infection caused by a group of bacteria called Burkholderia. |
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
The primary objective is to evaluate the safety and efficacy of continuous AZLI treatment in subjects with CF and Burkholderia spp. infection in the airways. |
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E.2.2 | Secondary objectives of the trial |
• Effect of continuous AZLI use on microbial resistance
• Suppressive effect of AZLI on Burkholderia spp.
• Safety of AZLI administered TID for up to 48 weeks |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥ 6 years of age
2. Subjects with CF as diagnosed by one of the following:
— Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test
— Documented sweat sodium ≥ 60 mmol/L
— Two well characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
— Abnormal NPD with accompanying symptoms characteristic of CF
3. Chronic infection with Burkholderia spp. defined by:
— One sputum (or bronchoalveolar lavage) culture positive for Burkholderia spp. within 6 months prior to baseline assessment,
— At least 50% of sputum (or bronchoalveolar lavage) cultures collected at least one month apart over the previous 12 months prior to baseline assessment positive for Burkholderia spp. (minimum of 2 positive cultures), and
— At least one positive sputum (or bronchoalveolar lavage) culture (obtained at any point in time) confirmed to be Burkholderia spp. by the CFF Burkholderia cepacia Research Laboratory and Repository at the University of Michigan (or equivalent Canadian reference laboratory)
Subjects with oro-pharyngeal cultures rather than sputum culture results available in the previous 12 months will meet the above criteria for chronic infection with Burkholderia spp. if:
— There is at least one documented prior lower respiratory tract culture(s) (expectorated, induced sputum or bronchoalveolar lavage) positive for Burkholderia spp. (obtained at any time point), and
— There is concordance of the species isolated from at least one prior lower respiratory tract cultures (obtained at any time point) and recent oropharyngeal cultures (obtained in the previous 12 months)
4. Concomitant aerosolized antibiotic treatment: subjects receiving intermittent (alternating month on/month off) aerosolized antibiotic treatment are eligible, but must be at least 1 week into their off-treatment cycle at the time of baseline assessment. Subjects receiving continuous aerosolized antibiotic treatment will be eligible without restriction
on their aerosolized antibiotic treatment
5. Chest radiograph, computed tomography (CT) or magnetic resonance imaging (MRI), (most recent, obtained within 90 days of screening) without significant acute findings (e.g., infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax), and no significant intercurrent illness; chronic, stable findings (e.g., chronic scarring or atelectasis) are allowed
6. Subjects (and parent/guardian as required) must be able to provide written informed consent/assent prior to any study related procedures
7. Ability to perform reproducible pulmonary function tests
8. Sexually active females of childbearing potential must agree to use a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of study drug; a highly effective method of birth control is defined as a method that results in a low failure rate (i.e., less than 1% per year)
when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), or a vasectomized partner |
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E.4 | Principal exclusion criteria |
1. Administration of any investigational drug or use of any investigational device within 28 days of randomization/baseline and within six half-lives of the investigational drug (whichever is longer)
2. Administration of AZLI treatment within the 28 days prior to randomization/baseline
3. Known local or systemic hypersensitivity to monobactam antibiotics
4. History of lung transplantation
5. Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as:
— AST or ALT > 5 times upper limit of normal (ULN) range
— Serum creatinine > 2 times ULN
6. Known portal hypertension or complications of CF hepatopathy
7. Positive urine pregnancy test (confirmed by serum pregnancy test) at screening; all women of childbearing potential will be tested
8. Female of childbearing potential who is lactating or not practicing a highly effective method of birth control as defined in Section 7.8
9. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with subject treatment, assessment or compliance with the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the relative change from baseline in FEV1 percent predicted as measured by the AUCave through Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• AUCave of relative change from baseline in FEV1, FVC, and FEF25-75 through Week 24
• AUCave of change from baseline in clinical symptoms as assessed by the respiratory symptoms domain of the CFQ-R through Week 24
• AUCave of change from baseline in clinical symptoms as assessed by the non-respiratory domains of the CFQ-R through Week 24
• Change from baseline in BMI at Week 24
• Change from baseline in Burkholderia spp. CFUs in sputum at Week 24
• Use of systemic antibiotics through Week 24 of the study
• Percent of days subjects used systemic antibiotics through Week 24 of the study
• Percent of days subjects were hospitalized through Week 24 of the study
• Percent of days lost from school or work through Week 24 of the study |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Two-part trial: 24 weeks double-blind placebo controlled followed by 24 weeks open label treatment. |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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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.8.9.2 | In all countries concerned by the trial years | 1 |